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Patent Analysis of

Peptides having anti-inflammatory properties

Updated Time 12 June 2019

Patent Registration Data

Publication Number

US10149886

Application Number

US15/286491

Application Date

05 October 2016

Publication Date

11 December 2018

Current Assignee

RIPTIDE BIOSCIENCE, INC.

Original Assignee (Applicant)

RIPTIDE BIOSCIENCE, INC.

International Classification

A61K38/08,A61K36/10,C07K7/06,A61K38/16,C07K14/00

Cooperative Classification

A61K38/08,C07K14/00,A61K31/337,A61K31/4745,A61K31/513

Inventor

JAYNES, JESSE,LOPEZ, HENRY WILFRED,MARTIN, GEORGE R.,YATES, CLAYTON,GARVIN, CHARLES

Patent Images

This patent contains figures and images illustrating the invention and its embodiment.

US10149886 Peptides anti-inflammatory properties 1 US10149886 Peptides anti-inflammatory properties 2 US10149886 Peptides anti-inflammatory properties 3
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Abstract

Aspects of the present invention relate to peptides having anti-inflammatory activity, compositions containing one or more of the peptides, and use of the peptides to treat conditions associated with excessive inflammation in animals, particularly humans and other mammals.

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Claims

1. An immunomodulatory peptide of 18 amino acid residues or less in length, wherein the peptide has a sequence defined by one of the formulae:

[Y1aY1b]-[X1aX1b]-[Y2aY2b]-[X2aX2b]-[Y3a]-[X3a]; and

[X3a]-[Y3a]-[X2bX2a]-[Y2bY2a]-[X1bX1a]-[Y1bY1a]; wherein: Y1a, Y1b, Y2a, Y2b and Y3a are each phenylalanine; and X1a, X1b, X2a, X2b and X3a are each independently selected from lysine and arginine.

2. The immunomodulatory peptide according to claim 1, wherein the striapathic region of the peptide has a length of 12 amino acid residues or less.

3. The immunomodulatory peptide according to claim 1, wherein the peptide comprises the amino acid sequence FFKKFFKKFK (SEQ ID NO:123).

4. The immunomodulatory peptide according to claim 2, wherein the peptide consists essentially of the amino acid sequence FFKKFFKKFK (SEQ ID NO:123).

5. The immunomodulatory peptide according to claim 1, wherein the peptide comprises the amino acid sequence KFKKFFKKFF (SEQ ID NO:124).

6. The immunomodulatory peptide according to claim 2, wherein the peptide consists essentially of the amino acid sequence KFKKFFKKFF (SEQ ID NO:124).

7. An immunomodulatory peptide of 18 amino acid residues or less in length, the peptide comprising the amino acid sequence KFKKAFKKAF (SEQ ID NO:148) or FFRKFAKRFK (SEQ ID NO:122).

8. The immunomodulatory peptide according to claim 7, wherein the peptide consists essentially of the amino acid sequence KFKKAFKKAF (SEQ ID NO:148).

9. The immunomodulatory peptide according to claim 7, wherein the peptide consists essentially of the amino acid sequence FFRKFAKRFK (SEQ ID NO:122).

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Claim Tree

  • 1
    1. An immunomodulatory peptide of 18 amino acid residues or less in length, wherein
    • the peptide has a sequence defined by one of the formulae: [Y1aY1b]-[X1aX1b]-[Y2aY2b]-[X2aX2b]-[Y3a]-[X3a]; and [X3a]-[Y3a]-[X2bX2a]-[Y2bY2a]-[X1bX1a]-[Y1bY1a]; wherein
    • 2. The immunomodulatory peptide according to claim 1, wherein
      • the striapathic region of the peptide has a length of 12 amino acid residues or less.
    • 3. The immunomodulatory peptide according to claim 1, wherein
      • the peptide comprises
    • 5. The immunomodulatory peptide according to claim 1, wherein
      • the peptide comprises
  • 7
    7. An immunomodulatory peptide of 18 amino acid residues or less in length, the peptide comprising
    • the amino acid sequence KFKKAFKKAF (SEQ ID NO:148) or FFRKFAKRFK (SEQ ID NO:122).
    • 8. The immunomodulatory peptide according to claim 7, wherein
      • the peptide consists essentially of the amino acid sequence KFKKAFKKAF (SEQ ID NO:148).
    • 9. The immunomodulatory peptide according to claim 7, wherein
      • the peptide consists essentially of the amino acid sequence FFRKFAKRFK (SEQ ID NO:122).
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Description

FIELD OF THE INVENTION

Aspects of the present invention relate to peptides having anti-inflammatory activity, compositions containing one or more of the peptides, and use of the peptides to treat conditions associated with excessive inflammation in animals, particularly humans and other mammals.

BACKGROUND OF THE INVENTION

Under normal conditions, inflammation is a process that helps an animal recover from injury. Acute inflammation is the initial response of a tissue to harmful stimuli. It involves a complex, highly regulated process that begins when cells present in the injured tissue, including macrophages, dendritic cells, histiocytes, Kupffer cells, and mastocytes, sense molecules associated with the injury and become activated. Upon activation, these cells release inflammatory mediators, such as vasodilators. The vasodilators induce increased blood flow and permeability of the blood vessels in the vicinity of the injury. This, in turn, results in the increased movement of plasma and leukocytes (including neutrophils and macrophages) from the blood into the injured tissue. Because inflammatory mediators are, in general, rapidly degraded, acute inflammation requires constant stimulation in order to be sustained. As a result, acute inflammation ends once the harmful stimulus is removed.

Various agents, including but not limited to bacteria, viruses, physical injury, chemical injury, cancer, chemotherapy, and radiation therapy, can, depending on the specific agent and the genetic makeup of the animal exposed to it, cause prolonged and excessive inflammation. Such inflammation, known as chronic inflammation, is believed to be a contributing factor to many widespread and debilitating diseases, including heart disease, cancer, respiratory disease, stroke, neurological diseases such as Alzheimer's disease, diabetes, and kidney disease. The result of chronic inflammation is the destruction of normal tissue and its replacement with collagen-rich connective tissue. Collagen-rich connective tissue, also known as scar tissue, exhibits diminished tissue function as compared to normal tissue. Persistent and prolonged formation of scar tissue, in turn, leads to fibrosis. Fibrosis is among the common symptoms of diseases affecting the lungs, skin, liver, heart, and bone marrow, and is a critical factor in diseases such as idiopathic pulmonary fibrosis, scleroderma, keloids, liver cirrhosis, myocardial fibrosis, diabetic kidney disease, myelodysplastic syndrome, and other disorders.

Studies of chronic inflammation and fibrosis have indicated that, regardless of the activating agent and the tissue affected, a common network of signaling proteins tend to function together to establish the pro-inflammatory state. This network of signaling proteins includes a number of different cytokines, cytokine receptors, transcription factors, and micro RNAs, including TGFβ, TGFβRII, and miRNA19b.

Despite growing knowledge about conditions that involve excessive inflammation, such as chronic inflammation and fibrosis, treatments for such conditions remain elusive. Many drugs and other substances have been shown to have anti-inflammatory activity, either in vitro or in vivo, but for many indications caused or potentiated by inflammation, there are still no therapies. In addition, many anti-inflammatory therapies are associated with harmful side effects. Thus, there remains a critical need to identify therapeutic agents that reduce inflammation without harmful side effects.

SUMMARY OF THE INVENTION

The present invention is based, in part, on the discovery of novel peptides that have powerful anti-inflammatory activities in vitro and in vivo. The present invention is also based, in part, on the discovery that peptides of the invention specifically bind to key functional regions on one or more signaling proteins, particularly pro-inflammatory cytokines, macrophage inhibition proteins, and histone regulation proteins. The present invention is also based, in part, on the discovery that the peptides of the invention are sufficiently stable in the circulation to allow for intravenous administration.

Accordingly, in one aspect, the invention provides a composition comprising an anti-inflammatory polypeptide. In certain embodiments, the anti-inflammatory polypeptide is 3 to 24 amino acids residues in length and includes a striapathic region consisting of alternating hydrophobic and hydrophilic modules. In certain embodiments, each hydrophilic module is made up of a sequence of one or more (e.g., 1-5, 1-4, 1-3) hydrophilic amino acid residues. In certain embodiments, each hydrophobic module is made up of a sequence of one or more (e.g., 1-5, 1-4, 1-3) hydrophobic amino acid residues.

In certain embodiments, the striapathic region of an anti-inflammatory peptide includes m hydrophilic modules and n hydrophobic modules, with m and n each being a positive integer. For example, in certain embodiments, the striapathic region includes two hydrophilic modules and two hydrophobic modules (2:2), two hydrophilic modules and three hydrophobic modules (2:3), three hydrophilic modules and two hydrophobic modules (3:2), three hydrophilic modules and three hydrophobic modules (3:3), three hydrophilic modules and four hydrophobic modules (3:4), or four hydrophilic modules and three hydrophobic modules (4:3).

In certain embodiments, the striapathic region of an anti-inflammatory polypeptide is at least 5, 6, 7, 8, 9, or 10 amino acid residues in length. In preferred embodiments, the length of the striapathic region is between 7 and 12 amino acid residues. In certain embodiments, the striapathic region makes up at least 25% of the length of the polypeptide. For example, in certain embodiments, the striapathic region comprises at least 30%, 35%, 40%, 45%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the length of the polypeptide.

In certain embodiments, the striapathic region of an anti-inflammatory polypeptide adopts a helical secondary structure. Examples of helical secondary structures include 310-helices, α-helices, π-helices, and poly-proline helices. In other embodiments, the striapathic region of an anti-inflammatory polypeptide adopts a beta-strand secondary structure. In preferred embodiments, the striapathic region of an anti-inflammatory polypeptides has an amphipathic conformation.

In certain embodiments, an anti-inflammatory polypeptide comprises, consists essentially of, or consists of a striapathic region having a sequence that conforms to any one of the structural formulas disclosed herein (e.g., any one of Formulas I-LIII). In certain embodiments, the anti-inflammatory polypeptide is one of the polypeptides listed in Tables 3-9. In other embodiments, the anti-inflammatory polypeptide has at least 70%, 80%, or 90% homology with any one of the polypeptides disclosed in Tables 3-9.

In certain embodiments, an anti-inflammatory polypeptide binds to at least one signaling protein. In preferred embodiments, the anti-inflammatory polypeptide binds to at least one signaling protein in vitro and/or in vivo, with sufficient affinity to modulate the activity of the signaling protein. Examples of signaling proteins that the anti-inflammatory polypeptides bind to include proteins that function as pro-inflammatory cytokines, proteins that inhibit macrophage activity, or protein that regulate histone function. In certain embodiments, the anti-inflammatory polypeptide binds to a protein target selected from the group consisting of NFkB class II proteins (e.g., Rel A, Rel B, cRel, NF-kB1, and NF-kB2). TGFβ, Notch receptors (e.g., Notch1), Wnt receptors (e.g., Wnt8R). TRAIL, EGFR, interleukin receptors (e.g., IL6R, IL10R), cyclin dependent kinases (e.g., CDK6), CD47, SIRP-α, transglutaminases (e.g., TGM2), LEGUMAIN, CD209, FAS, programmed cell death protein 1 (PD-1/CD279), mitogen-activated protein kinase kinase 7 (MKK7), ribonucleotide reductase (RNR), and histone methyl transferase. In preferred embodiments, the anti-inflammatory polypeptide binds to two, three, four, or more such signaling proteins. For example, in certain embodiments, an anti-inflammatory polypeptide binds to an NF-kB Class II protein (e.g., RelB) and at least one other signaling protein that functions as a pro-inflammatory cytokine, an inhibitor of macrophage activity, or a regulator of histone function. In preferred embodiments, the anti-inflammatory polypeptide binds to the NF-kB Class II protein and at least one other protein target, with sufficient binding affinity to each target to modulate the activity of both targets in vivo. In preferred embodiments, an anti-inflammatory polypeptide binds to the dimerization site of an NFkB Class II protein (e.g., RelB).

In certain embodiments, an anti-inflammatory polyeptides binds to a carrier protein in the blood (e.g., serum albumin).

In certain embodiments, an anti-inflammatory polypeptide is modified to include, for example, a linker, a carbohydrate, a lipid, or a polymer (e.g., PEG). In certain embodiments, a first anti-inflammatory polyeptide is linked to a second anti-inflammatory polypeptide so as to form a multimer, such as a dimer. In certain embodiments, the dimer is a homodimer. In other embodiments, the dimer is a heterodimer. In certain embodiments, the linker is a peptide linker. In preferred embodiments, the peptide linker forms a peptide bond with the C-terminus of the first anti-inflammatory polypeptide and a peptide bond with the N-terminus of the second anti-inflammatory polypeptide. In certain embodiments, the linker is a biodegradeable linker. In certain embodiments, the linker is a disulfide bond. In certain embodiments, the disulfide linkage is formed by a pair of cysteine residues (e.g., one cysteine residue from each of the polypeptides being linked).

In certain embodiments, the anti-inflammatory polypeptide is linked to a molecule other than another anti-inflammatory polypeptide. For example, the anti-inflammatory polypeptide can be linked to a label or a chemotherapeutic agent. In certain embodiments, the linker is a biodegradable linker. In certain embodiments, the linker is a di-sulfide bond (e.g., involving the sulfhydryl group of a cysteine residue located at the C-terminus or N-terminus of the anti-inflammatory polypeptide).

In another aspect, the invention provides pharmaceutical compositions that comprise an anti-inflammatory polypeptide and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a single type of anti-inflammatory polypeptide. In other embodiments, the pharmaceutical composition comprises a combination of two or more anti-inflammatory polypeptides. In preferred embodiments, the pharmaceutical composition is substantially free of blood proteins and/or metabolites found in the blood. In other embodiments, the pharmaceutical composition includes serum albumin (e.g., human serum albumin). In preferred embodiments, any serum albumin present in a pharmaceutical composition is recombinantly produced and/or substantially free of other blood proteins and/or metabolites found in the blood. In certain embodiments, the pharmaceutical composition comprises 1 mg to 1000 mg (e.g., 10 to 400 mg, 20 to 300 mg, or about 25 to 250 mg) of an anti-inflammatory polypeptide.

In another aspect, the invention provides methods of treating a subject by administering to the subject a composition (e.g., a pharmaceutical composition) comprising an anti-inflammatory polypeptide. In certain embodiments, the subject is an animal, such as a mammal (e.g., a human). In certain embodiments, the subject has elevated levels of inflammatory cytokines, is suffering from a chronic inflammatory condition, or is likely to develop a chronic inflammatory condition. In certain embodiments, the chronic inflammatory condition can be irritable bowel disease, ulcerative colitis, colitis, Crohn's disease, fibrosis, idiopathic pulmonary fibrosis, asthma, keratitis, arthritis, osteoarthritis, rheumatoid arthritis, an auto-immune disease, a feline or human immunodeficiency virus (FIV or HIV) infection, or cancer. In certain embodiments, the cancer is colon cancer, breast cancer, leukemia, lymphoma, ovarian cancer, prostate cancer, liver cancer, lung cancer, testicular cancer, cervical cancer, bladder cancer, endometrial cancer, kidney cancer, melanoma, or a cancer of the thyroid or brain. In certain embodiments, the composition is administered in combination with a chemotherapeutic agent, immunotherapeutic agent, and/or radiation therapy.

These and other features and advantages of the compositions and methods of the invention will be set forth or will become more fully apparent in the description that follows and in the appended claims. For example, suitable anti-inflammatory polypeptides may be identified by use of the Structural Algorithm described herein. Furthermore, features and advantages of the described compositions and methods may be learned by practicing the methods or will be obvious from the description.

BRIEF SUMMARY OF THE DRAWINGS

FIG. 1 depicts a structural model of human RelB, an NF-kB Class II protein.

FIG. 2 depicts a structural model of human RelB bound by RP-182.

FIG. 3 depicts a structural model of human RelB bound by RP-166.

FIG. 4 depicts a structural model of human RelB bound by RP-113.

FIG. 5 depicts a structural model of human RelB bound by RP-387.

FIG. 6 depicts a structural model of human RelB bound by RP-289.

FIG. 7 depicts a structural model of human RelB bound by NF-Contr2.

FIG. 8 depicts a structural model of human RelB bound by NF-Contr3.

FIG. 9 depicts structural models of polypeptides RP-182. RP-166, RP-113, and RP-289, with each model showing the polar and non-polar facial arc associated with the helices formed by the polypeptides.

FIG. 10 depicts structural models of polypeptides RP-387, NF-Contr2, and NF-Contr3, with each model showing the polar and non-polar amino acid residues. The facial arc associated with the helix formed by RP-387 is also shown.

FIG. 11 depicts a structural model of the binding pocket of the RelB dimerization domain.

FIG. 12 depicts a structural model of the binding pocket of the RelB dimerization domain bound by RP-183.

FIG. 13 depicts a structural model of histone methyl transferase enzyme bound by RP-182.

FIG. 14 depicts structural models of a CD47 dimer (left panel) and a CD47 dimer bound by RP-183.

FIG. 15 depicts structural models of a SIRP-α dimer (left panel) and a SIRP-α dimer bound by RP-183.

FIG. 16 depicts structural models of CD206 (left side) and CD206 bound by RP-182 (right side).

FIG. 17 depicts structural models of TGM2 (left side) and TGM2 bound by RP-182 (right side).

FIG. 18 depicts a structural model of human serum albumin bound by RP-183.

FIG. 19 shows PD-1-stained tumor cells from p53/KRAS mice treated with vehicle only (left panel) or treated with RP-182 (right panel). PD-1 expression is reduced in RP-182 treated mice.

FIG. 20 shows PD-L1-stained (left panels) and PD-L2-stained (right panels) tumor cells from p53/KRAS mice treated with vehicle only (top panel in each set) or treated with RP-182 (bottom panel in each set). PD-L1 and PD-L2 expression is reduced in RP-182 treated mice.

FIG. 21 shows MDA-MB-231 tumor volume in four cohorts of mice over time. Cohort 1: vehicle; Cohort 2: Gemcitabine treated; Cohort 3: RP-182 treated; Cohort 4: RP-182+Gemcitabine treated.

FIG. 22 shows C42B tumor volume in four cohorts of mice over time. Cohort 1: vehicle; Cohort 2: Docetaxel treated; Cohort 3: RP-182 treated; Cohort 4: RP-182+Docetaxel treated.

DETAILED DESCRIPTION OF THE INVENTION

The following description supplies specific details in order to provide a thorough understanding of the present invention. That said, to avoid obscuring aspects of the described anti-inflammatory polypeptides and related methods of treating a subject, well-known structures, materials, processes, techniques, and operations are not shown or described in detail. Additionally, the skilled artisan will understand that the described anti-inflammatory polypeptides and related methods of treating a subject can be implemented and used without employing these specific details. Indeed, the described anti-inflammatory polypeptides and methods can be placed into practice by modifying the illustrated polypeptides, compositions, and methods, and can be used in conjunction with other treatments, apparatuses, and techniques conventionally used in the industry.

As discussed above, the invention disclosed herein relates to immune-modulatory polypeptides, particularly peptides that have immunosuppressive properties, and methods of administering such immune-modulatory polypeptides to a subject, particularly a subject suffering from a medical condition associated with persistent inflammation or at risk developing such a medical condition.

The invention provides anti-inflammatory polypeptides, sometimes referred to as “RP peptides.” that satisfy the requirements of the Structural Algorithm described below. The invention also provides anti-inflammatory polypeptides that share a minimum degree of homology with any of the exemplary RP peptides disclosed herein. Thus, a peptide or polypeptide of the invention is an anti-inflammatory polypeptide that satisfies the Structural Algorithm described below or shares a minimum degree of homology with any of the exemplary RP peptides disclosed herein (e.g., in Tables 3-9).

The terms “peptide” and “polypeptide” are used synonymously herein to refer to polymers constructed from amino acid residues.

The term “amino acid residue,” as used herein, refers to any naturally occurring amino acid (L or D form), non-naturally occurring amino acid, or amino acid mimetic (such as a peptoid monomer).

The “length” of a polypeptide is the number of amino acid residues linked end-to-end that constitute the polypeptide, excluding any non-peptide linkers and/or modifications that the polypeptide may contain.

The term “striapathic region,” as used herein, refers to an alternating sequence of hydrophobic and hydrophilic modules. A “hydrophobic module” is made up of a peptide sequence consisting of one to five hydrophobic amino acid residues. Likewise, a hydrophilic module is made up of a peptide sequence consisting of one to five hydrophilic amino acid residues.

Hydrophobic amino acid residues are characterized by a functional group (“side chain”) that has predominantly non-polar chemical properties. Such hydrophobic amino acid residues can be naturally occurring (L or D form) or non-naturally occurring. Alternatively, hydrophobic amino acid residues can be amino acid mimetics characterized by a functional group (“side chain”) that has predominantly non-polar chemical properties. Conversely, hydrophilic amino acid residues are characterized by a functional group (“side chain”) that has predominantly polar (charged or uncharged) chemical properties. Such hydrophilic amino acid residues can be naturally occurring (L or D form) or non-naturally occurring. Alternatively, hydrophilic amino acid residues can be amino acid mimetics characterized by a functional group (“side chain”) that has predominantly polar (charged or uncharged) chemical properties. Examples of hydrophilic and hydrophobic amino acid residues are shown in Table 1, below. Suitable non-naturally occurring amino acid residues and amino acid mimetics are known in the art. See, e.g., Liang et al. (2013), “An Index for Characterization of Natural and Non-Natural Amino Acids for Peptidomimetics.” PLoS ONE 8(7):e67844.

Although most amino acid residues can be considered as either hydrophobic or hydrophilic, a few, depending on their context, can behave as either hydrophobic or hydrophilic. For example, due to their relatively weak non-polar characteristics, glycine, proline, and/or cysteine can sometimes function as hydrophilic amino acid residues. Conversely, due to their bulky, slightly hydrophobic side chains, histidine and arginine can sometimes function as hydrophobic amino acid residues.


TABLE 1
Hydrophobic and Hydrophilic Amino Acid Residues
Hydrophilic Residues
Hydrophobic Residues
(X)
(Y)
Arginine
Tryptophan
Histidine
Phenylalanine
Lysine
Tyrosine
Aspartic Acid
Isoleucine
Glutamic Acid
Leucine
Asparagine
Valine
Glutamine
Methionine
Pyrrolysine
Cysteine
Threonine
Serine
Alanine
Proline
Glycine
Selenocysteine
N-formylmethionine
Norleucine
Norvaline

The term “anti-inflammatory property,” as used herein, refers to any property of a polypeptide that can be evaluated in silico, in vitro, and/or in vivo, that reduces or inhibits, or would be expected to reduce or inhibit, a pro-inflammatory signal mediated by a protein target and/or reduces or inhibits inflammation in a subject.

Structural Algorithm

In its most basic form, the Structural Algorithm requires an anti-inflammatory peptide to have the following characteristics:

a length of 3 to 24 amino acid residues;

a striapathic region that comprises at least 25% of the length of the polypeptide; and

at least one anti-inflammatory property.

The anti-inflammatory peptide and/or its striapathic region can have a length that is greater than 3 amino acid residues and/or less than 24 amino acid residues. Thus, the requisite length of the polypeptide can be, for example, 3 to 20, 3 to 18, 3 to 16, 3 to 14, 3 to 12, 4 to 20, 4 to 18, 4 to 16, 4 to 14, 4 to 12, 5 to 20, 5 to 18, 5 to 16, 5 to 14, 5 to 12, 6 to 20, 6 to 18, 6 to 16, 6 to 14, 6 to 12, 7 to 20, 7 to 18, 7 to 16, 7 to 14, or in certain embodiments 7 to 12 amino acid residues. For an anti-inflammatory polypeptide that is longer than 12 amino acid residues, it can be advantageous to design a kink in the secondary structure (e.g., such as produced by a proline residue) such that the polypeptide has a striapathic region that is 12 or fewer amino acid residues in length. The striapathic region of an anti-inflammatory peptide can comprise at least 30%, 35%, 40%, 45%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the length of the polypeptide.

An anti-inflammatory polypeptide can have a striapathic region that includes at least two hydrophobic modules and one or more (e.g., two or three) hydrophilic modules. Alternatively, an anti-inflammatory polypeptide can have a striapathic region that includes at least three hydrophobic modules and two or more (e.g., three or four) hydrophilic modules; a striapathic region that includes at least two hydrophilic modules and one or more (e.g., two or three) hydrophilic modules; or a striapathic region that includes at least three hydrophilic modules and two or more (e.g., three or four) hydrophobic modules.

As discussed above, a striapathic region consists of alternating hydrophilic (Xm) and hydrophobic (Yn) modules. In this context, the subscripts m and n are positive integers that identify different modules. Each Xm module consists of a sequence according to the formula Xma-Xmb-Xmc-Xmd-Xme. Xma is selected from the group consisting of a naturally occurring hydrophilic amino acid, a non-naturally occurring hydrophilic amino acid, and a hydrophilic amino acid mimetic; and Xmb, Xmc, Xmd, and Xme are each individually absent or selected from the group consisting of a naturally occurring hydrophilic amino acid, a non-naturally occurring hydrophilic amino acid, and a hydrophilic amino acid mimetic. Each Yn module consists of a sequence according to the formula Yna-Ynb-Ync-Ynd-Yne. Yna is selected from the group consisting of a naturally occurring hydrophobic amino acid, a non-naturally occurring hydrophobic amino acid, and a hydrophobic amino acid mimetic; Ynb, Ync, Ynd, and Yne are each individually absent or selected from the group consisting of a naturally occurring hydrophobic, a non-naturally occurring hydrophobic amino acid, and a hydrophobic amino acid mimetic.

In certain anti-inflammatory polypeptides, each Xm module consists of a sequence according to the formula Xma-Xmb-Xmc-Xmd or Xma-Xmb-Xmc. Similarly, in certain anti-inflammatory polypeptides, each Yn module consists of a sequence according to the formula Yna-Ynb-Ync-Ynd or Yna-Ynb-Ync.

Anti-inflammatory peptides can include a striapathic region corresponding to a formula selected from the group consisting of:

Y1a-Y1b-Y1c-X1a-Y2a-Y2b-Y2c  (Formula I);

Y1a-Y1b-Y1c-X1a-Y2a-Y2b-Y2c-X2a-Y3a-X3a  (Formula II);

X2a-Y3a-X3a-Y1a-Y1b-Y1c-X1a-Y2a-Y2b-Y2c  (Formula III);

X1a-X1b-X1c-Y2a-X2a-X2b-X2c  (Formula IV);

Y1a-X1a-X1b-X1c-Y2a-X2a-X2b-X2c-Y3a-X3a  (Formula V);

X1a-X1b-Y2a-Y2b-X2a-X2b  (Formula VI);

Y1a-X1a-X1b-Y2a-Y2b-X2a-X2b-Y3a  (Formula VII);

Y1a-X1a-X1b-Y2a-Y2b-X2a-X2b-Y3a-Y3b-X3a  (Formula VIII);

Y1a-Y1b-X1a-X1b-Y2a-Y2b-X2a-X2b-Y3a-Y3b  (Formula IX);

Y1a-Y1b-X1a-X1b-Y2a-Y2b-X2a-X2b-Y3a-X3a  (Formula X);

X1a-Y1a-X2a-X2b-Y2a-Y2b-X3a-X3b-Y3a-Y3b  (Formula XI);

X1a-Y1a-Y1b-X2a-X2b-Y2a-Y2b-X3a-X3b-Y3a  (Formula XII);

Y1a-X1a-X1b-Y2a-Y2b-X2a-X2b-X2c-Y3a-Y3b  (Formula XIII);

X1a-X1b-X1c-Y1a-Y1b-X2a-X2b-Y2a-Y2b-Y2c  (Formula XIV);

Y1a-Y1b-Y1c-X1a-X1b-Y2a-Y2b-X2a-X2b-X2c  (Formula XV);

Y1a-Y1b-X1a-X1b-X1c-Y2a-Y2b-X2a-X2b-Y3a  (Formula XVI);

Y1a-Y1b-X1a-X1b-Y2a-Y2b  (Formula XVII);

X1a-Y1a-Y1b-X2a-X2b-Y2a-Y2b-X3a  (Formula XVIII);

Y1a-Y1b-X1a-X1b-Y2a-Y2b-X2a-Y3a-Y3b-X3a  (Formula XIX);

X1a-Y1a-Y1b-X2a-Y2a-Y2b-X3a-X3b-Y3a-Y3b  (Formula XX);

Y1a-Y1b-X1a-X1b-Y2a-X2a-X2b-Y3a-Y3b  (Formula XXI);

X1a-Y1a-Y1b-X2a-X2b-X2c-Y2a-X3a-Y3a-Y3b  (Formula XXII);

Y1a-Y1b-X1a-Y2a-X2a-X2b-X2c-Y3a-Y3b-X3a  (Formula XXIII);

X1a-X1b-Y1a-X2a-Y2a-X3a-X3b  (Formula XXIV);

Y1a-Y1b-Y1c-X1a-X1b-Y2a-X2a-Y3a-X3a-X3b  (Formula XXV);

X1a-X1b-Y1a-X2a-Y2a-X3a-X3b-Y3a-Y3b-Y3c  (Formula XXVI);

X1a-X1b-X1c-Y1a-Y1b-Y1c  (Formula XXVII);

X1a-X1b-X1c-X1d-Y1a-Y1b-Y1c-Y1d  (Formula XXVIII);

Y1a-X1a-X1b-X1c-X1d-Y2a-Y2b-Y2c-Y2d-X2a  (Formula XXIX);

X1a-X1b-X1c-X1d-X1e-Y1a-Y1b-Y1c-Y1d-Y1e  (Formula XXX);

Y1a-Y1b-X1a-X1b-X1c-Y2a-Y2b-Y2c-X2a-X2b  (Formula XXXI);

X1a-Y1a-X2a-Y2a-X3a-X3b-X3c-Y3a-Y3b-Y3c  (Formula XXXII);

Y1a-Y1b-Y1c-X1a-X1b-X1c  (Formula XXXIII);

Y1a-Y1b-Y1c-Y1d-X1a-X1b-X1c-X1d  (Formula XXXIV);

X1a-Y1a-Y1b-Y1c-Y1d-X2a-X2b-X2c-X2d-Y2a  (Formula XXXV);

Y1a-Y1b-Y1c-Y1d-Y1e-X1a-X1b-X1c-X1d-X1e  (Formula XXXVI);

X1a-X1b-Y1a-Y1b-Y1c-X2a-X2b-X2c-Y2a-Y2b  (Formula XXXVII);

Y1a-Y1b-Y1c-X1a-X1a-X1c-Y2a-X2a-Y3a-X3a  (Formula XXXVIII);

Y1a-X1b-X1b-X1c-X1d-X1e-Y2a  (Formula XXXIX);

Y1a-X1a-X1b-X1c-X1d-X1e-Y2a-Y2b-Y2c-Y2d  (Formula XL);

Y1a-Y1b-X1a-X1b-X1c-X1d-X1e-Y2a-Y2b-Y2c  (Formula XLI);

Y1a-Y1b-Y1c-X1a-X1b-X1c-X1d-X1e-Y2a-Y2b  (Formula XLII);

Y1a-Y1b-Y1c-Y1c-X1a-X1b-X1c-X1d-X1e-Y2a  (Formula XLIII);

X1a-Y1a-Y1b-Y1c-Y1d-Y1e-X2a  (Formula XLIV);

X1a-Y1a-Y1b-Y1c-Y1d-Y1e-X2a-X2b-X2c-X2d  (Formula XLV);

X1a-X1b-Y1a-Y1b-Y1c-Y1d-Y1e-X2a-X2b-X2c  (Formula XLVI);

X1a-X1b-X1c-Y1a-Y1b-Y1c-Y1d-Y1e-X2a-X2b  (Formula XLVII);

X1a-X1b-X1c-X1d-Y1a-Y1b-Y1c-Y1d-Y1e-X2a  (Formula XLVIII);

Y1a-X1a-Y2a-X2a-Y3a-X3a  (Formula XLIX);

Y1a-Y1b-X1a-Y2a-Y2b-X2a-Y3a-Y3b-X3a-Y4a  (Formula L);

X1a-X1b-Y1a-Y1b-X2a-Y2a-Y2b-Y2c-Y2d  (Formula LI);

Y1a-Y1b-Y1c-Y1d-X1a-Y2a-Y2b-X2a-X2b  (Formula LII);

Y1a-Y1b-X1a-Y2a-Y2b-Y2c-X2b-Y3a-X3a-Y4a  (Formula LIII); and

Y1a-X1a-Y2a-X2a-Y3a-Y3b-Y3c-X3a-Y4a-Y4b  (Formula LIV).

Typically, the striapathic region (or a portion thereof) of an anti-inflammatory polypeptide will have an amphipathic conformation (e.g., under physiological conditions). To be considered amphipathic, the striapathic region (or portion thereof) need not be in the amphipathic conformation at all times. Rather, it is sufficient that the amphipathic conformation be present at least 50%, 60%, 70%, 80%, or more of the time, or when the anti-inflammatory polypeptide is binding to a target molecule, such as an NF-kB Class II protein (e.g., Rel B). Often, the amphipathic conformation will be associated with a particular secondary structure, such as a helical structure. Thus, the striapathic region (or a portion thereof) of the anti-inflammatory polypeptide can have an amphipathic 310-helical conformation, an amphipathic α-helical conformation, an amphipathic π-helical conformation, or an amphipathic poly-proline helical conformation. Alternatively, the striapathic region (or a portion thereof) of the anti-inflammatory polypeptide can have an amphipathic β-strand conformation.

For anti-inflammatory peptides that comprise a striapathic region that includes or has an amphipathic helical conformation (e.g., 310-helical, α-helical, π-helical, or polyproline helical conformation), the hydrophobic surface (“side”) can have a facial arc of at least 100°. In certain embodiments, the facial arc of the hydrophobic surface or side is at least 125°, 150°, 175°, 200°, 225°, 250°, 275°, or 300°.

Anti-inflammatory polypeptides in certain embodiments have a striapathic region that has a relatively large hydrophobic volume. Accordingly, the striapathic region can optimally contain hydrophobic amino acid residues having a total side-chain volume of at least 600 cubic angstroms. In certain embodiments, the hydrophobic amino acid residues of the striapathic region have a hydrophobic side-chain volume of at least 650, 700, 750, 800, 850, 900, 950, 1000, or more cubic angstroms. Alternatively, or in addition, the striapathic region can be characterized by a ratio of the sum of the side-chain volume of hydrophobic amino acid residues to the sum of the side-chain volume of hydrophilic amino acid residues, wherein the ratio is at least 0.75 or higher. For example, the ratio can be at least 0.8, 0.85, 0.9, 0.95, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, or greater.

Because of the desirability of a striapathic region having a relatively large hydrophobic side-chain volume, it is generally preferable to include one or more (e.g., 2, 3, 4, 5, or more) large hydrophobic amino acid residues in the sequence of the striapathic region. Conversely, it is generally preferable to have two or fewer (e.g., 1 or 0) small hydrophobic amino acid residues in the sequence of the striapathic region. Examples of large hydrophobic amino acid residues include tryptophan, phenylalanine, and tyrosine. In addition, under certain circumstances, histidine or arginine can be considered a large hydrophobic amino acid residue. Examples of small hydrophobic residues include glycine, alanine, serine, cysteine, valine, threonine, and proline. Accordingly, an anti-inflammatory polypeptide can have a striapathic region that includes one or more (e.g., 2, 3, 4, 5, or more) hydrophobic residues selected from the group consisting of tryptophan, phenylalanine, and tyrosine. Alternatively, the anti-inflammatory polypeptide can have a striapathic region that includes one or more (e.g., 2, 3, 4, 5, or more) hydrophobic residues selected from (i) the group consisting of tryptophan, phenylalanine, tyrosine, and histidine, or (ii) the group consisting of tryptophan, phenylalanine, tyrosine, and arginine. In certain embodiments, the anti-inflammatory polypeptide has a striapathic region that includes two or fewer (e.g., 1 or 0) hydrophobic residues selected from the group consisting of glycine, alanine, serine, cysteine, valine, threonine, and proline. Alternatively, the anti-inflammatory polypeptide can have a striapathic region that includes no more than one hydrophobic residue selected from the group consisting of glycine, alanine, serine, cysteine, valine, threonine, and proline. In other alternatives, the anti-inflammatory polypeptide can have a striapathic region that includes no glycine residues, no alanine residues, no scrine residues, no cysteine residues, no valine residues, no threonine residues, and/or no proline residues.

It is also preferable that an anti-inflammatory polypeptide have a striapathic region characterized by a moderate level of cationicity (i.e., a striapathic region that does not contain an excessive number of amino acid residues having positively charged side chains). Examples of amino acid residues having positively charged side groups (assuming physiological conditions) includes lysine, typically arginine, and sometimes histidine. Examples of amino acid residues having negatively charged side chains (assuming physiological conditions) include aspartic acid and glutamic acid. Examples of hydrophilic amino acid residues having uncharged side chains (assuming physiological conditions) include aspargine and glutamine. Accordingly, an anti-inflammatory polypeptide can have a striapathic region that includes five or fewer (e.g., 4, 3, 2) lysine residues. Alternatively, an anti-inflammatory polypeptide can have a striapathic region that includes five or fewer (e.g., 4, 3, 2) amino acid residues selected from the group consisting of lysine and arginine. In other alternatives, an anti-inflammatory polypeptide can have a striapathic region that includes five or fewer (e.g., 4, 3, 2) amino acid residues selected from the group consisting of lysine, arginine, and histidine. For anti-inflammatory polypeptides that have a striapathic region that includes one or more (e.g., two or more) positively charged amino acid residues, it can be advantageous for the striapathic region to also include some negatively charged or polar, uncharged amino acid residues. For example, the anti-inflammatory polypeptide can have a striapathic region that includes both positively and negatively charged amino acid residues, such that the net charge on the polypeptide is no more than +2 or +1 (e.g., the number of positively charged amino acid residues does not exceed the number of negatively charged amino acid residues by more than one or two). Alternatively, the anti-inflammatory polypeptide can have a striapathic region that includes both positively charged and polar, uncharged amino acid residues, such that the net charge on the polypeptide is no more than +2 or +1 (e.g., the number of positively charged amino acid residues does not exceed one or two). In other alternatives, the anti-inflammatory polypeptide can have a striapathic region that includes both positively charged, negatively charged, and hydrophilic uncharged charged amino acid residues, such that the net charge on the polypeptide is no more than +2.

To avoid certain undesired interactions between RP peptides and other molecules (whether another RP peptide, a metal ion, etc.) it can be advantageous to limit the number of certain types of amino acid residues in the polypeptide. For example, because cysteine residues form di-sulfide bonds under certain conditions (e.g., oxidative environments), it can be useful to limit the number of cysteine residues in a polypeptide of the invention to no more than one or two, or even none. Because histidine residues chelate metals under certain conditions (e.g., alkaline environments), it can be useful to limit the number of histidine residues in a polypeptide of the invention to no more than one or two, or even none. In addition, because proline residues tend to introduce kinks into secondary structure elements (e.g., α-helices and β-strands), it can be useful exclude proline residues in the striapathic region of a polypeptide of the invention, or limit their number to no more than one.

Class I Polypeptides

An anti-inflammatory polypeptide of the invention can be a Class I polypeptide. Class I polypeptides comprise, consist essentially of, or consist of a striapathic region that includes a sequence selected from the group of sequences defined by Formula I:

Y1a-Y1b-Y1c-X1a-Y2a-Y2b-Y2c  (Formula I).

Each of amino acid residues Y1a, Y1b, Y1c, Y2a, Y2b, and Y2c in Formula I can be selected from the group consisting of Phe (F), Trp (W), Tyr (Y), His (H), Leu (L), Cys (C), Met (M), Val (V), Ile (I), Pro (P), Thr (T), Ser (S), Ala (A), and Gly (G). In certain embodiments, at least 3, 4, 5, or 6 of amino acid residues Y1a, Y1b, Y1c, Y2a, Y2b, and Y2c in Formula I are selected from the group consisting of Phe (F), Trp (W), Tyr (Y), His (H), and Leu (L). In certain embodiments, at least 3, 4, 5, or 6 of amino acid residues Y1a, Y1b, Y1c, Y2a, Y2b, and Y2c in Formula I are selected from the group consisting of Phe (F), Trp (W), and Tyr (Y). In certain embodiments, less than two (and in certain embodiments 1 or none) of amino acid residues Y1a, Y1b, Y1c, Y2a, Y2b, and Y2c in Formula I are selected from the group consisting of Pro (P), Thr (T), Ser (S), Ala (A), and Gly (G).

The module Y1a-Y1b-Y1c in Formula I can have a sequence selected from the group consisting of Phe-Phe-Phe (FFF), Trp-Trp-Trp (WWW), Tyr-Tyr-Tyr (YYY), Leu-Leu-Leu (LLL), Cys-Cys-Cys (CCC), Met-Met-Met (MMM), Val-Val-Val (VVV), Ile-Ile-Ile (III). Alternatively, the module Y1a-Y1b-Y1c in Formula I can have a sequence selected from the group consisting of Pro-Pro-Pro (PPP), Thr-Thr-Thr (TTT), and Ala-Ala-Ala (AAA). In certain embodiments, module Y1a-Y1b-Y1c in Formula I has a sequence selected from the group consisting of Phe-Phe-Phe (FFF), Trp-Trp-Trp (WWW), Tyr-Tyr-Tyr (YYY), and combinations thereof (e.g., Phe-Phe-Trp (FFW), Phe-Trp-Trp (FWW), Trp-Phe-Trp (WFW), Trp-Trp-Phe (WWF), Phe-Phe-Tyr (FFY), Phe-Tyr-Tyr (FYY), Tyr-Phe-Tyr (YFY), Tyr-Tyr-Phe (YYF), Trp-Trp-Tyr (WWY), Trp-Tyr-Tyr (WYY), Tyr-Trp-Tyr (YWY), Tyr-Tyr-Trp (YYW), Phe-Trp-Tyr (FWY), Phe-Tyr-Trp (FYW), Trp-Phe-Tyr (WFY), Trp-Tyr-Phe (WYF), Tyr-Trp-Phe (YWF), or Tyr-Phe-Trp (YFW)).

The module Y2a-Y2b-Y2c in Formula I can have a sequence selected from the group consisting of Phe-Phe-Phe (FFF), Trp-Trp-Trp (WWW), Tyr-Tyr-Tyr (YYY), Leu-Leu-Leu (LLL), Cys-Cys-Cys (CCC), Met-Met-Met (MMM), Val-Val-Val (VVV), and Ile-Ile-Ile (III). Alternatively, the module Y2a-Y2b-Y2c in Formula I can have a sequence selected from the group consisting of Pro-Pro-Pro (PPP), Thr-Thr-Thr (TTT), and Ala-Ala-Ala (AAA). In certain embodiments, module Y2a-Y2b-Y2c in Formula I has a sequence selected from the group consisting of Phe-Phe-Phe (FFF), Trp-Trp-Trp (WWW), Tyr-Tyr-Tyr (YYY), and combinations thereof (e.g., Phe-Phe-Trp (FFW), Phe-Trp-Trp (FWW), Trp-Phe-Trp (WFW), Trp-Trp-Phe (WWF), Phe-Phe-Tyr (FFY), Phe-Tyr-Tyr (FYY), Tyr-Phe-Tyr (YFY), Tyr-Tyr-Phe (YYF), Trp-Trp-Tyr (WWY), Trp-Tyr-Tyr (WYY), Tyr-Trp-Tyr (YWY), Tyr-Tyr-Trp (YYW), Phe-Trp-Tyr (FWY), Phe-Tyr-Trp (FYW), Trp-Phe-Tyr (WFY), Trp-Tyr-Phe (WYF), Tyr-Trp-Phe (YWF), or Tyr-Phe-Trp (YFW)).

Thus, a Class I anti-inflammatory polypeptide can comprise, consist essentially of, or consist of a striapathic region having a sequence selected from the group consisting of FFF-X1a-FFF (SEQ ID NO: 1). WWW-X1a-WWW (SEQ ID NO: 2), YYY-X1a-YYY (SEQ ID NO: 3), and combinations thereof. Alternatively, a Class I anti-inflammatory polypeptide can comprise, consist essentially of, or consist of a striapathic region having a sequence selected from the group consisting of LLL-X1a-LLL (SEQ ID NO: 4). CCC-X1a-CCC (SEQ ID NO: 5), MMM-X1a-MMM (SEQ ID NO: 6), VVV-X1a-VVV (SEQ ID NO: 7), and III-X1a-III (SEQ ID NO: 8). In such peptides, X1a can be selected from the group consisting of Arg (R), His (H), and Lys (K); or X1a can be selected from the group consisting of Glu (E), Gln (Q), Asn (N), and Asp (D).

A Class I anti-inflammatory polypeptide can comprise, consist essentially of, or consist of a striapathic region having a sequence selected from the group of sequences defined by Formula II or the group of sequences defined by Formula III:

Y1a-Y1b-Y1c-X1a-Y2a-Y2b-Y2c-X2a-Y3a-X3a  (Formula II);

X2a-Y3a-X3a-Y1a-Y1b-Y1c-X1a-Y2a-Y2b-Y2c  (Formula III).

The Y1a-Y1b-Y1c-X1a-Y2a-Y2b-Y2c sequences defined by Formulas II and III can be any of the sequences described above in connection with Formula I. X2a and X3a in Formulas II and III can be each individually selected from the group consisting of Arg (R), His (H), Lys (K), Glu (E), Gln (Q), Asn (N), and Asp (D). Alternatively, X2a and X3a in Formulas II and III can be each individually selected from the group consisting of Arg (R), His (H), and Lys (K). In other alternatives, X2a and X3a in Formulas II and III can be each individually selected from the group consisting of Arg (R), His (H), Lys (K), and Gln (Q). In other alternatives, X2a and X3a in Formulas II and III can be each individually selected from the group consisting Glu (E), Gln (Q), Asn (N), and Asp (D). In other alternatives, X2a in Formulas II and III can be selected from the group consisting of Arg (R), His (H), and Lys (K), and X3a in Formulas II and III can be selected from the group consisting of Glu (E), Gln (Q), Asn (N), and Asp (D). Y3a in Formulas II and III can be selected from the group consisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val (V), and Ile (I). In certain embodiments, Y3a in Formulas II and III is selected from the group consisting of Phe (F), Trp (W), Tyr (Y), and Leu (L).

The modules X2a-Y3a-X3a in Formulas II and III can be selected from the group consisting of EFQ, EFE, EFN, EFD, NFQ. NFE. NFN, NFD, QFQ, QFE, QFN, QFD, DFQ, DFE, DFN, DFD, EWQ, EWE, EWN, EWD, NWQ, NWE, NWN, NWD, QWQ, QWE, QWN, QWD, DWQ, DWE, DWN, DWD, EYQ, EYE, EFN, EYD, NYQ, NYE, NYN, NYD, QYQ, QYE, QYN, QYD, DYQ, DYE, DYN, DYD, ELQ, ELE, ELN, ELD, NLQ, NLE, NLN, NLD, QLQ, QLE, QLN, QLD, DLQ, DLE, DLN, DLD, RFR, RFQ, RFE, RFN, RFD, RWR, RWQ, RWE, RWN, and RWD.

A Class I anti-inflammatory polypeptide can comprise, consist essentially of, or consist of a striapathic region comprising, consisting essentially of, or consisting of a sequence selected from the group of sequences listed in Table 3, e.g., RP394, RP108-RP123, RP125-131, RP133, RP135-RP141, RP143-RP146, RP148-RP150, RP152-RP165, RP179, RP395, RP211, RP230, RP232, RP258, RP267, RP268, RP271, RP273, RP280-281, and RP287. In certain embodiments, the Class I anti-inflammatory polypeptide can comprise, consist essentially of, or consist of a striapathic region that comprises, consists essentially of, or consists of a sequence selected from the group of sequences consisting of RP113 (SEQ ID NO: 39), RP118 (SEQ ID NO: 44), and RP394 (SEQ ID NO: 33).

Class II Polypeptides

An anti-inflammatory polypeptide of the invention can be a Class II polypeptide. Class II anti-inflammatory polypeptides can comprise, consist essentially of, or consist of a striapathic region that includes a sequence selected from the group of sequences defined by Formula VII:

Y1a-X1a-X1b-Y2a-Y2b-X2a-X2b-Y3a  (Formula VII).

Amino acid residue Y2a in Formula VII can be selected from the group consisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val (V), Ile (I), Pro (P), Thr (T), Ser (S), Ala (A), and Gly (G). In certain embodiments, amino acid residue Y2a in Formula VII is selected from the group consisting of Phe (F), Trp (W), and Tyr (Y). Alternatively, amino acid residue Y2a in Formula VII can be selected from the group consisting of Leu (L), Cys (C), Met (M), Val (V), Ile (I).

Amino acid residue Y2b in Formula VII can be selected from the group consisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val (V), Ile (I), Pro (P), Thr (T), Ser (S), Ala (A), and Gly (G). In certain embodiments, amino acid residue Y2b in Formula VII is selected from the group consisting of Phe (F), Trp (W), and Tyr (Y). Alternatively, amino acid residue Y2b in Formula VII can be selected from the group consisting of Leu (L), Cys (C), Met (M), Val (V), Ile (I).

Amino acid residue X1b in Formula VII can be selected from the group consisting of Arg (R), Lys (K), and His (H). Alternatively amino acid residue X1b in Formula VII can be selected from the group consisting of Asn (N), Gln (Q), Asp (D), and Glu (E).

Amino acid residue X2a in Formula VII can be selected from the group consisting of Arg (R), Lys (K), and His (H). Alternatively, amino acid residue X2a can be selected from the group consisting of Asn (N), Gln (Q), Asp (D), and Glu (E).

The sequence X1b-Y2a-Y2b-X2a in Formula VII can be selected from the group consisting of Lys-Phe-Phe-Lys (KFFK; SEQ ID NO: 386), Lys-Trp-Trp-Lys (KWWK; SEQ ID NO: 387), Lys-Tyr-Try-Lys (KYYK; SEQ ID NO: 388), Lys-Phe-Trp-Lys (KFWK; SEQ ID NO: 389), Lys-Trp-Phe-Lys (KWFK; SEQ ID NO: 390), Lys-Phe-Tyr-Lys (KFYK; SEQ ID NO: 391), Lys-Tyr-Phe-Lys (KYFK; SEQ ID NO: 392), Lys-Trp-Tyr-Lys (KWYK; SEQ ID NO: 393), and Lys-Tyr-Trp-Lys (KYWK; SEQ ID NO: 394). Alternatively, the sequence X1b-Y2a-Y2b-X2a in Formula VII can be selected from the group consisting of Arg-Phe-Phe-Arg (RFFR; SEQ ID NO: 395), Arg-Trp-Trp-Arg (RWWR; SEQ ID NO: 396), Arg-Tyr-Try-Arg (RYYR; SEQ ID NO: 397), Arg-Phe-Trp-Arg (RFWR; SEQ ID NO: 398), Arg-Trp-Phe-Arg (RWFR; SEQ ID NO: 399), Arg-Phe-Tyr-Arg (RFYR; SEQ ID NO: 400), Arg-Tyr-Phe-Arg (RYFR; SEQ ID NO: 401), Arg-Trp-Tyr-Arg (RWYR; SEQ ID NO: 402), and Arg-Tyr-Trp-Arg (RYWR; SEQ ID NO: 403). In other alternatives, the sequence X1b-Y22-Y2b-X2a in Formula VII can be selected from the group consisting of His-Phe-Phe-His (HFFH; SEQ ID NO: 404), His-Trp-Trp-His (HWWH; SEQ ID NO: 405), His-Tyr-Try-His (HYYH; SEQ ID NO: 406), His-Phe-Trp-His (HFWH; SEQ ID NO: 407), His-Trp-Phe-His (HWFH; SEQ ID NO: 408), His-Phe-Tyr-His (HFYH; SEQ ID NO: 409), His-Tyr-Phe-His (HYFH; SEQ ID NO: 410), His-Trp-Tyr-His (HWYH; SEQ ID NO: 411), and His-Tyr-Trp-His (HYWH; SEQ ID NO:132).

Amino acid residue X1a in Formula VII can be selected from the group consisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), and Glu (E). In certain embodiments, amino acid residue X1a is selected from the group consisting of Arg (R) and Gln (Q). In certain embodiments, amino acid residue X1a in Formula VII is Arg (R). Alternatively, amino acid residue X1a in Formula VII can be selected from the group consisting of Lys (K), Gln (Q), Glu (E), and Asn (N).

Amino acid residue X2b in Formula VII can be selected from the group consisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), and Glu (E). In certain embodiments, amino acid residue X2b is selected from the group consisting of Arg (R) and Gln (Q). In certain embodiments, amino acid residue X2b in Formula VII is Arg (R). Alternatively, amino acid residue X2b in Formula VII can be selected from the group consisting of Lys (K), Gln (Q), Glu (E), and Asn (N).

Amino acid residue Y1a in Formula VII can be selected from the group consisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val (V), Ile (I), Thr (T), Pro (P), Ser (S), Ala (A), and Gly (G). In certain embodiments, amino acid residue Y1a in Formula VII is selected from the group consisting of Phe (F), Trp (W), and Tyr (Y). Alternatively, amino acid residue Y1a in Formula VII can be selected from the group consisting of Leu (L), Cys (C), Met (M), Val (V), Ile (I).

Amino acid residue Y3a in Formula VII can be selected from the group consisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val (V), Ile (I), Thr (T), Pro (P), Ser (S), Ala (A), and Gly (G). In certain embodiments, amino acid residue Y3a in Formula VII is selected from the group consisting of Phe (F), Trp (W), and Tyr (Y). Alternatively, amino acid residue Y3a in Formula VII can be selected from the group consisting of Leu (L), Cys (C), Met (M), Val (V), Ile (I).

Thus, a Class II anti-inflammatory polypeptide can comprise, consist essentially of, or consist of a striapathic region having a sequence selected from the group consisting of F-X1a-X1b-FF-X2a-X2b-F (SEQ ID NO: 9), F-X1a-X1b-FF-X2a-X2b-W (SEQ ID NO: 10), W-X1a-X1b-FF-X2a-X2b-F (SEQ ID NO: 11), F-X1a-X1b-FW-X2a-X2b-F (SEQ ID NO: 12), F-X1a-X1b-WF-X2a-X2b-F (SEQ ID NO: 13), F-X1a-X1b-WW-X2a-X2b-F (SEQ ID NO: 14), W-X1a-X1b-WW-X2a-X2b-F (SEQ ID NO: 15), F-X1a-X1b-WW-X2a-X2b-W (SEQ ID NO: 16), W-X1a-X1b-WW-X2a-X2b-W (SEQ ID NO: 17), F-X1a-X1b-FF-X2a-X2b-Y (SEQ ID NO: 18), Y-X1a-X1b-FF-X2a-X2b-F (SEQ ID NO: 19), F-X1a-X1b-FY-X2a-X2b-F (SEQ ID NO: 20), F-X1a-X1b-YF-X2a-X2b-F (SEQ ID NO: 21), F-X1a-X1b-YY-X2a-X2b-F (SEQ ID NO: 22), Y-X1a-X1b-YY-X2a-X2b-F (SEQ ID NO: 23), F-X1a-X1b-YY-X2a-X2b-Y (SEQ ID NO: 24), and Y-X1a-X1b-YY-X2a-X2b-Y (SEQ ID NO: 25), Y-X1a-X1b-YY-X2a-X2b-W (SEQ ID NO: 26), W-X1a-X1b-YY-X2a-X2b-Y (SEQ ID NO: 27), Y-X1a-X1b-YW-X2a-X2b-Y (SEQ ID NO: 28), Y-X1a-X1b-WY-X2a-X2b-Y (SEQ ID NO: 29), Y-X1a-X1b-WW-X2a-X2b-Y (SEQ ID NO: 30), W-X1a-X1b-WW-X2a-X2b-Y (SEQ ID NO: 31), and Y-X1a-X1b-WW-X2a-X2b-W (SEQ ID NO: 32). Amino acid residues X1a, X1b, X2a, and X2b in the foregoing sequences can be selected as discussed above.

A Class II anti-inflammatory polypeptide can comprise, consist essentially of, or consist of a striapathic region that further includes a first additional amino acid residue directly bound to amino acid residue Y1a of Formula VII. The first additional amino acid residue can be a hydrophobic amino acid residue (e.g., a residue selected from the group consisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val (V), Ile (I), Thr (T), Pro (P), Ser (S), Ala (A), and Gly (G); a residue selected from the group consisting of Phe (F), Trp (W), and Tyr (Y); a residue selected from the group consisting of Phe (F), Trp (W), Tyr (Y), and Leu (L); or, a residue selected from the group consisting of Leu (L), Cys (C), Met (M), Val (V), and Ile (I)). Alternatively, the first additional amino acid residue can be a hydrophilic amino acid residue (e.g., a residue selected from the group consisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), and Glu (E); a residue selected from the group consisting of Arg (R), Lys (K), and His (H); a residue selected from the group consisting Arg (R), Lys (K), His (H), and Gln (Q); or a residue selected from the group consisting of Asn (N), Gln (Q), Asp (D), and Glu (E)).

A Class II anti-inflammatory polypeptide can comprise, consist essentially of, or consist of a striapathic region that further includes a first additional amino acid residue directly bound to amino acid residue Y3a of Formula VII. The first additional amino acid residue can be a hydrophobic amino acid residue (e.g., a residue selected from the group consisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val (V), Ile (I), Thr (T), Pro (P), Ser (S), Ala (A), and Gly (G); a residue selected from the group consisting of Phe (F), Trp (W), and Tyr (Y); a residue selected from the group consisting of Phe (F), Trp (W), Tyr (Y), and Leu (L); or, a residue selected from the group consisting of Leu (L), Cys (C), Met (M), Val (V), and Ile (I)). Alternatively, the first additional amino acid residue can be a hydrophilic amino acid residue (e.g., a residue selected from the group consisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), and Glu (E); a residue selected from the group consisting of Arg (R), Lys (K), and His (H); a residue selected from the group consisting Arg (R), Lys (K), His (H), and Gln (Q); or a residue selected from the group consisting of Asn (N), Gln (Q), Asp (D), and Glu (E)).

A Class II anti-inflammatory polypeptide can comprise, consist essentially of, or consist of a striapathic region that further includes a first additional amino acid residue directly bound to amino acid residue Y1a of Formula VII and a second additional amino acid reside directly bound to amino acid residue Y3a of Formula VII. The first additional amino acid residue can be a hydrophobic amino acid residue and the second additional amino acid residue can be a hydrophilic amino acid residue. Alternatively, the first additional amino acid residue can be a hydrophilic amino acid residue and the second amino acid residue can be a hydrophobic amino acid residue. Regardless, the additional hydrophobic amino acid residue can be selected from the group consisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val (V), Ile (I), Thr (T), Pro (P), Ser (S), Ala (A), and Gly (G); and in certain embodiments from the group consisting of Phe (F), Trp (W), and Tyr (Y); and in additional embodiments from the group consisting of Phe (F). The additional hydrophilic amino acid residue can be selected from the group consisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), and Glu (E); and in certain embodiments, a residue selected from the group consisting of Arg (R), Lys (K), and His (H); or a residue selected from the group consisting of Asn (N), Gln (Q), Asp (D), and Glu (E).

A Class II anti-inflammatory polypeptide can comprise, consist essentially of, or consist of a striapathic region comprising, consisting essentially of, or consisting of a sequence selected from the group of sequences listed in Table 5, e.g., RP124, RP132, RP134, RP142, RP147, RP151, RP166-RP172, RP175, RP177, RP182, RP183, RP185, RP186, RP424, RP190, RP194, RP198, RP199-RP202, RP204, RP206, RP207, RP209, RP210, RP212-RP216, RP218, RP219, RP425, RP225, RP227, RP233-RP239, RP398, RP241-RP247, RP250-RP256, RP426, RP427, RP285, and RP387. In certain embodiments, the Class II anti-inflammatory polypeptide comprises, consists essentially of, or consists of a striapathic region comprising, consisting essentially of, or consisting of a sequence selected from the group consisting of RP124 (SEQ ID NO: 106), RP166 (SEQ ID NO: 112), RP182 (SEQ ID NO: 121), and RP183 (SEQ ID NO: 122).

Class XII Polypeptides

An anti-inflammatory polypeptide of the invention can be a Class XII polypeptide. Class XII anti-inflammatory polypeptides can comprise, consist essentially of, or consist of a striapathic region that includes a sequence selected from the group of sequences defined by Formula XLIX:

Y1a-X1a-Y2a-X2a-Y3a-X3a  (Formula XLIX).

Amino acid residues Y1a, Y2a, and Y3a of Formula XLIX can be each independently selected from the group consisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Ile (I), Cys (C), Met (M), Val (V), Pro (P), Thr (T), Ser (S), Ala (A), and Gly (G). In certain embodiments, amino acid residues Y1a, Y2a, and Y3a of Formula XLIX are each independently selected from: the group consisting of Phe (F), Trp (W), and Tyr (Y); the group consisting of Phe (F), Trp (W), Tyr (Y), and Leu (L); or the group consisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Ile (I), Cys (C), Met (M), Val (V), and Ala (A).

Amino acid residues X1a, X2a, and X3a of Formula XLIX can be each independently selected from the group consisting of Arg (R), Lys (K), His (H), Gln (Q), Glu (E), Asn (N), and Asp (D). In certain embodiments, amino acid residues X1a, X2a, and X3a are each independently selected from the group consisting of Arg (R), Lys (K), and His (H). Alternatively, amino acid residues X1a, X2a, and X3a are each independently selected from the group consisting of Arg (R), Lys (K), His (H), and Gln (Q).

A Class XII anti-inflammatory polypeptide can comprise, consist essentially of, or consist of a striapathic region that further includes a first additional amino acid residue. The first additional amino acid residue can be a hydrophilic amino acid residue directly bound to amino acid residue Y1a of Formula XLIX. Thus, the first additional amino acid residue can be, for example, a residue selected from the group consisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), and Glu (E); a residue selected from the group consisting of Arg (R), Lys (K), and His (H); a residue selected from the group consisting Arg (R), Lys (K), His (H), and Gln (Q); or a residue selected from the group consisting of Asn (N), Gln (Q), Asp (D), and Glu (E)). Alternatively, the first amino acid residue can be a hydrophobic amino acid residue directly bound to amino acid residue X3a of Formula XLIX. Thus, the first additional amino acid residue can be, for example, a residue selected from the group consisting of Phe (F), Trp (W), and Tyr (Y); a residue selected from the group consisting of Phe (F), Trp (W), Tyr (Y), and Leu (L); or a residue selected from the group consisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Ile (I), Cys (C), Met (M), Val (V), and Ala (A)).

A Class XII anti-inflammatory polypeptide can comprise, consist essentially of, or consist of a striapathic region that further includes first and second additional amino acid residues. The first additional amino acid residue can be a hydrophilic amino acid residue, as discussed above, which is directly bound to amino acid residue Y1a of Formula XLIX. The second additional amino acid residue can be directly bound to the first additional amino acid residue. Thus, the second additional amino acid residue can be a hydrophobic amino acid residue, e.g., a residue selected from the group consisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val (V), Ile (I), Thr (T), Pro (P), Ser (S), Ala (A), and Gly (G); a residue selected from the group consisting of Phe (F), Trp (W), and Tyr (Y); a residue selected from the group consisting of Phe (F), Trp (W), Tyr (Y), and Leu (L); or, a residue selected from the group consisting of Leu (L), Cys (C), Met (M), Val (V), and Ile (I)). Alternatively, the second additional amino acid residue can be a hydrophobic amino acid residue directly bound to amino acid residue X3a of Formula XLIX, as discussed above.

A Class XII anti-inflammatory polypeptide can comprise, consist essentially of, or consist of a striapathic region that further includes first, second, and third additional amino acid residues. The first additional amino acid residue can be a hydrophilic amino acid residue which is directly bound to amino acid residue Y1a of Formula XLIX and the second additional amino acid residue can be a hydrophobic amino acid residue which is directly bound to the first additional amino acid residue, as discussed above. The third additional amino acid residue can be a hydrophilic amino acid residue that is directly bound to the second additional amino acid residue. Thus, the third additional amino acid residue can be, for example, a residue selected from the group consisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), and Glu (E); a residue selected from the group consisting of Arg (R), Lys (K), and His (H); a residue selected from the group consisting Arg (R), Lys (K), His (H), and Gln (Q); or a residue selected from the group consisting of Asn (N), Gln (Q), Asp (D), and Glu (E)). Alternatively, the third amino acid residue can be a hydrophobic amino acid residue directly bound to amino acid residue X3a of Formula XLIX. Thus, the third additional amino acid residue can be, for example, a residue selected from the group consisting of Phe (F), Trp (W), and Tyr (Y); a residue selected from the group consisting of Phe (F), Trp (W), Tyr (Y), and Leu (L); or a residue selected from the group consisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Ile (I), Cys (C), Met (M), Val (V), and Ala (A)).

A Class XII anti-inflammatory polypeptide can comprise, consist essentially of, or consist of a striapathic region that further includes four, five, six, or more additional amino acid residues. The additional amino acid residue can be added in a manner that continues the alternating patter of a hydrophobic amino acid residue followed by a hydrophilic amino acid residue followed by a hydrophobic amino acid residue, as shown in Formula XLIX. In this manner, Class XII anti-inflammatory polypeptides can be expanded to comprise, consist essentially of, or consist of a striapathic region having 10, 11, 12, or more amino acid residues.

An anti-inflammatory polypeptide of Class XII can comprise, consist essentially of, or consist of a striapathic region comprising, consisting essentially of, or consisting of a sequence selected from the group consisting of RP393, RP391, PR392, RP390, and RP389.

Class XIV Polypeptides

An anti-inflammatory polypeptide of the invention can be a Class XIV polypeptide. Class XIV anti-inflammatory polypeptides can comprise, consist essentially of, or consist of a striapathic region that includes a sequence selected from the group of sequences defined by any one of Formulas LI through LIV:

X1a-X1b-Y1a-Y1b-X2a-Y2a-Y2b-Y2c-Y2d  (Formula LI);

Y1a-Y1b-Y1c-Y1d-X1a-Y2a-Y2b-X2a-X2b  (Formula LII);

Y1a-Y1b-X1a-Y2a-Y2b-Y2c-X2b-Y3a-X3a-Y4a  (Formula LIII); and

Y1a-X1a-Y2a-X2a-Y3a-Y3b-Y3c-X3a-Y4a-Y4b  (Formula LIV).

The striapathic region of a Class XIV polypeptide can include at least 3 (e.g., 3 to 6) proline amino acid residues. For example, amino acid residues Y1a, Y2a, and Y2b in Formula LI can be proline amino acid residues. Alternatively, amino acid residues Y1c, Y1d, and Y2b in Formula LII can be proline amino acid residues. In other alternatives, amino acid residues Y1a, Y2a, Y2b, Y2c, Y3a, and Y4a in Formula LIII can be proline amino acid residues. In still other alternatives, amino acid residues Y1a, Y2b, Y3a, Y3b, Y3c, and Y4b in Formula LIV can be proline amino acid residues.

Hydrophobic amino acid residues (e.g., Y1a, Y1b, Y1c, Y1d, Y2a, Y2b, Y2c, Y2d, Y3a, Y3b, Y3c, Y4a, and Y4b) not designated as proline residues in Formulas LI through LIV can be each individually selected from the group consisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val (V), Ile (I), Thr (T), Pro (P), Ser (S), Ala (A), and Gly (G). In certain embodiments, such hydrophobic amino acid residues are each individually selected from: the group consisting of Phe (F), Trp (W), and Tyr (Y); the group consisting of Phe (F), Trp (W), Tyr (Y), and Leu (L); or, the group consisting of Leu (L), Cys (C), Met (M), Val (V), and Ile (I)).

Hydrophilic amino acid residues in Formulas LI through LIV (e.g., X1a, X1b, X2a, X2b, and X3a) can be each individually selected from the group consisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), and Glu (E). In certain embodiments, such hydrophilic amino acid residues are each individually selected from the group consisting of Arg (R), Lys (K), and His (H). Alternatively, such hydrophilic amino acid residues are each individually selected from: the group consisting of Arg (R), Lys (K), His (H), and Gln (Q); or the group consisting of Asn (N), Gln (Q), Asp (D), and Glu (E).

An anti-inflammatory polypeptide of Class XIV can comprise, consist essentially of, or consist of a striapathic region that comprises, consists essentially of, or consists of a sequence selected from the group consisting of RP449, RP450, RP448, RP447, RP452, RP451, RP444, RP441, RP446, RP445, RP442, and RP443.

Other Classes of Polypeptides

An anti-inflammatory polypeptide of the invention can be from any of Classes II through XI and XIII. Such anti-inflammatory polypeptides can comprise, consist essentially of, or consist of a striapathic region that includes a sequence selected from the group of sequences defined by any one of Formulas IV through XLVIII and L.

Hydrophobic amino acid residues in Formulas IV through XLVIII and L (e.g., Y1a, Y1b, Y1c, Y1d, Y1e, Y2a, Y2b, Y2c, Y2d, Y2e, Y3a, Y3b, Y3c, Y4a and Y4b) can be each individually selected from the group consisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val (V), Ile (I), Thr (T), Pro (P), Ser (S), Ala (A), and Gly (G). In certain embodiments, such hydrophobic amino acid residues are each individually selected from: the group consisting of Phe (F), Trp (W), and Tyr (Y); the group consisting of Phe (F), Trp (W), Tyr (Y), and Leu (L); or, the group consisting of Leu (L), Cys (C), Met (M), Val (V), and Ile (I)).

Hydrophilic amino acid residues in Formulas IV through XLVIII and L (e.g., X1a, X1b, X1c, X1d, X2a, X2b, X2c, X2d, X3a, X3b, X3c, X4a, and X4b) can be each individually selected from the group consisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), and Glu (E). In certain embodiments, such hydrophilic amino acid residues are each individually selected from the group consisting of Arg (R), Lys (K), and His (H). Alternatively, such hydrophilic amino acid residues are each individually selected from: the group consisting of Arg (R), Lys (K), His (H), and Gln (Q); or the group consisting of Asn (N), Gln (Q), Asp (D), and Glu (E).

An anti-inflammatory polypeptide of any one of Formulas IV through XLVIII and L can comprise, consist essentially of, or consist of a striapathic region that further includes a first additional amino acid residue directly bound to the first amino acid residue of the Formula (e.g., Y1a or X1a) or to the last amino acid residue in the formula. The first additional amino acid residue can be a hydrophilic amino acid residue (e.g., a residue selected from the group consisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), and Glu (E); a residue selected from the group consisting of Arg (R), Lys (K), and His (H); a residue selected from the group consisting Arg (R), Lys (K), His (H), and Gln (Q); or a residue selected from the group consisting of Asn (N), Gln (Q), Asp (D), and Glu (E)). Alternatively, the first additional amino acid residue can be a hydrophobic amino acid residue (e.g., a residue selected from the group consisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val (V), Ile (I), Thr (T), Pro (P), Ser (S), Ala (A), and Gly (G); a residue selected from the group consisting of Phe (F), Trp (W), and Tyr (Y); a residue selected from the group consisting of Phe (F), Trp (W), Tyr (Y), and Leu (L); or, a residue selected from the group consisting of Leu (L), Cys (C), Met (M), Val (V), and Ile (I)).

An anti-inflammatory polypeptide of any one of Formulas IV through XLVIII and L can comprise, consist essentially of, or consist of a striapathic region that further includes first and second additional amino acid residues, with the first additional amino acid residue directly bound to the first amino acid residue of the Formula (e.g., Y1a or X1a) or the last amino acid residue in the formula, and the second additional amino acid residue directly bound to the first amino acid residue in the formula, the last amino acid residue in the formula, or the first additional amino acid residue. The first additional amino acid residue can be a hydrophilic or hydrophobic amino acid residue, as discussed above. The second additional amino acid residue likewise can be a hydrophilic or hydrophobic amino acid residue, as discussed above.

An anti-inflammatory polypeptide of any one of Formulas IV through XLVIII and L can comprise, consist essentially of, or consist of a striapathic region that comprises, consists essentially of, or consists of a sequence selected from the group consisting of RP396, RP405, RP174, RP176, RP178, RP180-181, RP184, RP408, RP187, RP416, RP188, RP189, RP388, RP417, RP191-RP193, RP404, RP196, RP397, RP197, RP402, RP203, RP409, RP205, RP208, RP217, RP220-RP224, RP226, RP229, RP231, RP240, RP248, RP249, RP415, RP257, RP259-RP266, RP269, RP272, RP274, RP277-RP279, RP282, RP283, RP286, RP289, and RP414.

Variant Polypeptides

The exemplary anti-inflammatory polypeptide sequences shown in Tables 3-9 (below) are merely examples and are not the only anti-inflammatory polypeptides provided herein. Indeed, fragments and variants of the sequences of the disclosed peptides are within the scope of the invention.

A “fragment” of the invention includes at least 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 contiguous amino acid residues of a polypeptide disclosed herein (or up to one less than the number of amino acid residues in the subject polypeptide) and retains at least one anti-inflammatory property of the subject polypeptide. Thus, fragments of the invention include polypeptides that are missing one, two, three, four, or more amino acids from the N-terminus and/or the C-terminus relative to a polypeptide disclosed herein.

A “variant” of the invention is a polypeptide that is substantially similar to a polypeptide disclosed herein and retains at least one anti-inflammatory property of the subject polypeptide. Variants can include deletions (i.e., truncations) of one or more amino acid residues at the N-terminus or the C-terminus of a subject polypeptide disclosed herein; deletion and/or addition of one or more amino acid residues at one or more internal sites in the subject polypeptide disclosed herein; and/or substitution of one or more amino acid residues at one or more positions in the subject polypeptide disclosed herein. For subject polypeptides that are 12 amino acid residues in length or shorter, variant polypeptides can include three or fewer (e.g., two, one, or none) deleted amino acid residues, whether located internally, at the N-terminal end, and/or at the C-terminal end.

Accordingly, the invention further provides anti-inflammatory polypeptides that are at least 50% identical (e.g., at least 60%, 70%, 80%, 90%, or more) to any one of the anti-inflammatory polypeptides disclosed in Tables 3-9 and still retain at least one anti-inflammatory property. For example, the invention provides anti-inflammatory polypeptides that are 3 to 24 amino acids residues in length and comprise, consist essentially of, or consist of a striapathic region sharing at least 50% identity (e.g., at least 60%, 70%, 80%, 90%, or more identity) with a Class I anti-inflammatory polypeptide (e.g., any one of the sequences of Table 3). Such identity can be shared, for example, with RP-394 (SEQ ID NO: 33), RP-108 (SEQ ID NO: 34), RP-113 (SEQ ID NO: 39), RP-118 (SEQ ID NO: 44), RP-129 (SEQ ID NO: 54), or RP-179 (SEQ ID NO: 86). Alternatively, the invention provides anti-inflammatory polypeptides that are 3 to 24 amino acid residues in length and comprise, consist essentially of, or consist of a striapathic region sharing at least 50% identity (e.g., at least 60%, 70%, 80%, 90%, or more identity) with a Class II, Sub-class 1 anti-inflammatory polypeptide (e.g., any one of the sequences of Table 5). Such identity can be shared, for example, with RP-124 (SEQ ID NO: 106), RP-134 (SEQ ID NO: 108), RP-166 (SEQ ID NO: 112), RP-168 (SEQ ID NO: 114), RP-182 (SEQ ID NO: 121), or RP-183 (SEQ ID NO: 122). In other alternatives, the invention provides anti-inflammatory polypeptides that are 3 to 24 amino acid residues in length and comprise, consist essentially of, or consist of a striapathic region sharing at least 50% identity (e.g., at least 60%, 70%, 80%, 90%, or more identity) with any Class II through Class IX or Class XIII anti-inflammatory polypeptide (e.g., any one of the sequences of Table 6). In other alternatives, the invention provides anti-inflammatory polypeptides that are 3 to 24 amino acid residues in length and comprise, consist essentially of, or consist of a striapathic region sharing at least 50% identity (e.g., at least 60%, 70%, 80%, 90%, or more identity) with any Class VIII to Class XI anti-inflammatory polypeptide (e.g., any one of the sequences of Table 7). In other alternatives, the invention provides anti-inflammatory polypeptides that are 3 to 24 amino acid residues in length and comprise, consist essentially of, or consist of a striapathic region sharing at least 50% identity (e.g., at least 60%, 70%, 80%, 90%, or more identity) with a Class XII or Class XIV anti-inflammatory polypeptide (e.g., any one of the sequences of Table 8). In still other alternatives, the invention provides anti-inflammatory polypeptides that are 3 to 24 amino acid residues in length and comprise, consist essentially of, or consist of a striapathic region sharing at least 50% identity (e.g., at least 60%, 70%, 80%, 90%, or more identity) with any one of the combination sequences of Table 9.

The differences between the striapathic region of a homologous anti-inflammatory polypeptide and any one of the anti-inflammatory polypeptides of Tables 3-9 can include deletions, additions, and/or substitutions of amino acid residues, as discussed above. Substituted amino acid residues can be unrelated to the amino acid residue being replaced (e.g., unrelated in terms or hydrophobicity/hydrophilicity, size, charge, polarity, etc.), or the substituted amino acid residues can constitute similar, conservative, or highly conservative amino acid substitutions. As used herein. “similar,”“conservative,” and “highly conservative” amino acid substitutions are defined as shown in Table 2, below. The determination of whether an amino acid residue substitution is similar, conservative, or highly conservative is based exclusively on the side chain of the amino acid residue and not the peptide backbone, which may be modified to increase peptide stability, as discussed below.


TABLE 2
Classification of Amino Acid Substitutions
Highly
Similar
Conservative
Conservative
Amino Acid in
Amino Acid
Amino Acid
Amino Acid
Subject Polypeptide
Substitutions
Substitutions
Substitutions
Glycine (G)
A, S, N
A
n/a
Alanine (A)
S, G, T, V, C, P, Q
S, G, T
S
Serine (S)
T, A, N, G, Q
T, A, N
T, A
Threonine (T)
S, A, V, N, M
S, A, V, N
S
Cysteine (C)
A, S, T, V, I
A
n/a
Proline (P)
A, S, T, K
A
n/a
Methionine (M)
L, I, V, F
L, I, V
L, I
Valine (V)
I, L, M, T, A
I, L, M
I
Leucine (L)
M, I, V, F, T, A
M, I, V, F
M, I
Isoleucine (I)
V, L, M, F, T, C
V, L, M, F
V, L, M
Phenylalanine (F)
W, L, M, I, V
W, L
n/a
Tyrosine (Y)
F, W, H, L, I
F, W
F
Tryptophan (W)
F, L, V
F
n/a
Asparagine (N)
Q
Q
Q
Glutamine (Q)
N
N
N
Aspartic Acid (D)
E
E
E
Glutamic Acid (E)
D
D
D
Histidine (H)
R, K
R, K
R, K
Lysine (K)
R, H
R, H
R, H
Arginine (R)
KH
K, H
K, H

In certain embodiments, a variant polypeptide of the invention binds to two or more targets (e.g., pro-inflammatory targets). In some embodiments, a variant polypeptide binds to three, four, five, or more pro-inflammatory targets. For example, a variant polypeptide can bind to any combination of targets disclosed herein (e.g., an NF-kB Class II protein and human serum albumin (HSA)), as discussed below. Such binding can be based on in silico, in vitro, or in vivo data.

Modeling Polypeptide Binding to Target Molecules

The determination of whether a polypeptide has anti-inflammatory properties can be performed in silico. For example, the binding of a polypeptide (e.g., a polypeptide that has a length of 3 to 24 amino acid residues and includes a striapathic region comprising at least 25% of the length of the polypeptide) to a putative target molecule can be modeled in silico, using any of the numerous molecular modeling and docking platforms available in the art, to thereby assess whether the polypeptide is an anti-inflammatory polypeptide. The on-line ClusPro™ algorithm, version 2.0 (developed at Boston University) is particularly useful for modeling the conformation of polypeptides and their binding to target molecules, such as signaling proteins, as described in the Examples set forth below. Modeling algorithms, such as the ClusPro™ algorithm, that allow for docking of polypeptides on target molecules can be used, for example, to predict the binding energy associated with the polypeptide-target interaction. Such predictions provide reasonable estimates for the binding energies, but they are not necessarily equal to the binding energies that would be calculated by testing the polypeptides and protein targets in vitro. In that regard, the binding energies identified herein were all generated using the ClusPro™ algorithm. Accordingly, absent indication to the contrary, any numerical reference to the binding energy associated with a peptide binding to a particular target is a reference to a binding energy determined by modeling the interaction using the ClusPro™ algorithm.

As detailed in the Examples below, the exemplary RP peptides have been shown to interact with various signaling molecules associated with inflammation, including NF-kB Class II subunit RelB. TGFβ, Notch1, Wnt8R, TRAIL, IL6R, IL10R, EGFR, and CDK6, as well as other membrane associated signaling molecules, including CD206, CD47 and SIRP-α, translational modification protein transglutaminase 2 (TGM2), and histone modification enzyme histone methyl transferase (HMT). Upon folding of these protein targets to their normal 3-dimensional conformations, an amphipathic cleft is often generated that has high affinity for the immune-modulating peptides herein described.

For modeling interactions between potential anti-inflammatory polypeptides and NF-kB Class II subunits, any Class II subunit sequence can be used (e.g., RelA, RelB, cRel, NF-kB1, or NF-kB2). In certain embodiments, the Class II subunit sequence folds into a functional Class II subunit or a functional fragment thereof. The particular Class II subunit used for modeling can be selected based on the type of subject that the anti-inflammatory polypeptide is intended to treat (e.g., a human NF-kB Class II subunit is selected if the intended subject is a human, a bovine NF-kB Class II subunit is selected if the intended subject is a cow, etc.). The NF-kB Class II subunit sequence used for modeling can be the human RelB sequence (NCBI Accession No. NP-006500), which is as follows:


(SEQ ID NO: 367)
MLRSGPASGPSVPTGRAMPSRRVARPPAAPELGALGSPDLSSLSLAVSRSTDELEIIDEYIKENG
FGLDGGQPGPGEGLPRLVSRGAASLSTVTLGPVAPPATPPPWGCPLGRLVSPAPGPGPQPHLVIT
EQPKQRGMRFRYECEGRSAGSILGESSTEASKTLPAIELRDCGGLREVEVTACLVWKDWPHRVHP
HSLVGKDCTDGICRVRLRPHVSPRHSFNNLGIQCVRKKEIEAAIERKIQLGIDPYNAGSLKNHQE
EPLPFTYLPRDHDSYGVDKKRKRGMPDVLGELNSSDPHGIESKRRKKKPAILDHFLPNHGSGPFL
PPSALLPDPDFFSGTVSLPGLEPPGGPDLLDDGFAYDPTAPTLFTMLDLLPPAPPHASAVVCSGG
AGAVVGETPGPEPLTLDSYQAPGPGDGGTASLVGSNMFPNHYREAAFGGGLLSPGPEAT.

The underlined sequence in human RelB (above) has been identified as the dimerization domain. The highlighted amino acid residues (Tyr-300, Leu-302, and His-332) are believed to be particularly important in the dimerization interaction.

An anti-inflammatory polypeptide can be identified based on its ability to bind (e.g., in silico) to the dimerization pocket of the Class II subunit and/or interfere with or block the ability of the Class II subunit to dimerize. For example, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human RelB (SEQ ID NO: 367) selected from the group consisting of Leu-281, Ile-283, Cys-284, Glu-298, Tyr-300, Leu-301, Leu-302, Cys-303, Ile-311, Ser-312, Ala-329, Asp-330, Val-331, His-332, Gln-334, and Leu-371, or the equivalent amino acid residue(s) in a different human NF-kB Class 11 protein or an NF-kB Class II protein of another species. Alternatively, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human RelB (SEQ ID NO: 367) selected from the group consisting of Glu-298, Tyr-300, Leu-302, Asp-330, Gln-334, and Leu-371 or the equivalent amino acid residue(s) in a different human NF-kB Class II protein or an NF-kB Class II protein of another species.

In certain embodiments, an anti-inflammatory polypeptide binds to human RelB (SEQ ID NO: 367) with an affinity of at least −650 kcal/mol, and in certain embodiments at least −700, −750, −800, −850, −900, −925, −950, −975, −1000, −1025, −1050, −1075, −1100, −1125, −1150, −1200 kcal/mol, or greater. The requisite binding affinity can correspond to a binding affinity that can be detected in vitro or in vivo. Alternatively, the requisite binding affinity can correspond to a binding affinity that can be detected in silico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatory polypeptides and TGFβ, any TGFβ protein sequence can be used. The TGFβ sequence generally folds into a functional TGFβ protein or a functional fragment thereof. The TGFβ protein sequence used for modeling can be selected based on the type of subject that the anti-inflammatory polypeptide is intended to treat (e.g., a human TGFβ is selected if the intended subject is a human, a bovine TGFβ is selected if the intended subject is a cow, etc.). The sequence used for modeling can be the human TGFβ sequence (NCBI Acc. No. NP_000651.3), which is as follows:


(SEQ ID NO: 368)
MPPSGLRLLPLLLPLLWLLVLTPGRPAAGLSTCKTIDMELVKRKRIEAIR
GQILSKLRLASPPSQGEVPPGPLPEAVLALYNSTRDRVAGESAEPEPEPE
ADYYAKEVTRVLMVETHNEIYDKFKQSTHSIYMFFNTSELREAVPEPVLL
SRAELRLLRLKLKVEQHVELYQKYSNNSWRYLSNRLLAPSDSPEWLSFDV
TGVVRQWLSRGGEIEGFRLSAHCSCDSRDNTLQVDINGFTTGRRGDLATI
HGMNRPFLLMATPLERAQHLQSSRHRRALDTNYCFSSTEKNCCVRQLYID
FRKDLGWKWIHEPKGYHANFCLGPCPYIWSLDTQYSKVLALYNQHNPGAS
AAPCCVPQALEPLPIVYYVGRKPKVEQLSNMIVRSCKCS.

An anti-inflammatory polypeptide can be identified, for example, based on its ability to bind to the receptor binding site on TGFβ and/or interfere with or block the ability of TGFβ to bind to its receptor. For example, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human TGFβ (SEQ ID NO: 368) selected from the group consisting of Arg-25, Gly-29, Trp-30, Lys-31, Trp-32, Ile-33, His-34, Tyr-91, Val-92, Val-93, Gly-94, Arg-95, Lys-96, and Pro-97, or the equivalent amino acid residue(s) in a TGFβ protein of another species. Alternatively, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human TGFβ (SEQ ID NO: 368) selected from the group consisting of Leu-20, Ile-22, Phe-24, Asp-27, Leu-28, Trp-30, Trp-32, Tyr-39, Phe-43, Pro-80, Leu-83, Leu-101 and Ser-112, or the equivalent amino acid residue(s) in a TGFβ protein of another species. In other alternatives, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human TGFβ (SEQ ID NO: 368) selected from the group consisting of Asp-27, Leu-28, Trp-30, and Trp-32, or the equivalent amino acid residue(s) in a TGFβ protein of another species.

In certain embodiments, an anti-inflammatory polypeptide can bind to human TGFβ (SEQ ID NO: 368) with an affinity of at least −650 kcal/mol, and in certain embodiments at least −700, −750, −800, −850, −900, −925, −950, −975, −1000, −1025, −1050 kcal/mol, or greater. The requisite binding affinity can correspond to a binding affinity that can be detected in vitro or in vivo. Alternatively, the requisite binding affinity can correspond to a binding affinity that can be detected in silico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatory polypeptides and Notch1, any Notch1 protein sequence can be used. The Notch1 sequence used for modeling generally folds into a functional Notch1 protein or a calcium-binding fragment thereof. The Notch1 sequence used for modeling can be selected based on the type of subject that the anti-inflammatory polypeptide is intended to treat (e.g., a human Notch1 is selected if the intended subject is a human, a bovine Notch1 is selected if the intended subject is a cow, etc.). The sequence used for modeling can be the human Notch1 sequence (GenBank Acc. No. AAG33848.1), which is as follows:


(SEQ ID NO: 369)
MPPLLAPLLCLALLPALAARGPRCSQPGETCLNGGKCEAANGTEACVCGG
AFVGPRCQDPNPCLSTPCKNAGTCHVVDRRGVADYACSCALGFSGPLCLT
PLDNACLTNPCRNGGTCDLLTLTEYKCRCPPGWSGKSCQQADPCASNPCA
NGGQCLPFEASYICHCPPSFHGPTCRQDVNECGQKPRLCRHGGTCHNEVG
SYRCVCRATHTGPNCERPYVPCSPSPCQNGGTCRPTGDVTHECACLPGFT
GQNCEENIDDCPGNNCKNGGACVDGVNTYNCPCPPEWTGQYCTEDVDECQ
LMPNACQNGGTCHNTHGGYNCVCVNGWTGEDCSENIDDCASAACFHGATC
HDRVASFYCECPHGRTGLLCHLNDACISNPCNEGSNCDTNPVNGKAICTC
PSGYTGPACSQDVDECSLGANPCEHAGKCINTLGSFECQCLQGYTGPRCE
IDVNECVSNPCQNDATCLDQIGEFQCMCMPGYEGVHCEVNTDECASSPCL
HNGRCLDKINEFQCECPTGFTGHLCQYDVDECASTPCKNGAKCLDGPNTY
TCVCTEGYTGTHCEVDIDECDPDPCHYGSCKDGVATFTCLCRPGYTGHHC
ETNINECSSQPCRLRGTCQDPDNAYLCFCLKGTTGPNCEINLDDCASSPC
DSGTCLDKIDGYECACEPGYTGSMCNSNIDECAGNPCHNGGTCEDGINGF
TCRCPEGYHDPTCLSEVNECNSNPCVHGACRDSLNGYKCDCDPGWSGTNC
DINNNECESNPCVNGGTCKDMTSGIVCTCREGFSGPNCQTNINECASNPC
LNKGTCIDDVAGYKCNCLLPYTGATCEWLAPCAPSPCRNGGECRQSEDYE
SFSCVCPTAGAKGQTCEVDINECVLSPCRHGASCQNTHGXYRCHCQAGYS
GRNCETDIDDCRPNPCHNGGSCTDGINTAFCDCLPGFRGTFCEEDINECA
SDPCRNGANCTDCVDSYTCTCPAGFSGIHCENNTPDCTESSCFNGGTCVD
GINSFTCLCPPGFTGSYCQHVVNECDSRPCLLGGTCQDGRGLHRCTCPQG
YTGPNCQNLVHWCDSSPCKNGGKCWQTHTQYRCECPSGWTGLYCDVPSVS
CEVAAQRQGVDVARLCQHGGLCVDAGNTHHCRCQAGYTGSYCEDLVDECS
PSPCQNGATCTDYLGGYSCKCVAGYHGVNCSEEIDECLSHPCQNGGTCLD
LPNTYKCSCPRGTQGVHCEINVDDCNPPVDPVSRSPKCFNNGTCVDQVGG
YSCTCPPGFVGERCEGDVNECLSNPCDARGTQNCVQRVNDFHCECRAGHT
GRRCESVINGCKGKPCKNGGTCAVASNTARGFICKCPAGFEGATCENDAR
TCGSLRCLNGGTCISGPRSPTCLCLGPFTGPECQFPASSPCLGGNPCYNQ
GTCEPTSESPFYRCLCPAKFNGLLCHILDYSFGGGAGRDIPPPLIEEACE
LPECQEDAGNKVCSLQCNNHACGWDGGDCSLNFNDPWKNCTQSLQCWKYF
SDGHCDSQCNSAGCLFDGFDCQRAEGQCNPLYDQYCKDHFSDGHCDQGCN
SAECEWDGLDCAEHVPERLAAGTLVVVVLMPPEQLRNSSFHFLRELSRVL
HTNVVFKRDAHGQQMIFPYYGREEELRKHPIKRAAEGWAAPDALLGQVKA
SLLPGGSEGGRRRRELDPMDVRGSIVYLEIDNRQCVQASSQCFQSATDVA
AFLGALASLGSLNIPYKIEAVQSETVEPPPPAQLHFMYVAAAAFVLLFFV
GCGVLLSRKRRRQHGQLWFPEGFKVSEASKKKRREPLGEDSVGLKPLKNA
SDGALMDDNQNEWGDEDLETKKFRFEEPVVLPDLDDQTDHRQWTQQHLDA
ADLRMSAMAPTPPQGEVDADCMDVNVRGPDGFTPLMIASCSGGGLETGNS
EEEEDAPAVISDFIYQGASLHNQTDRTGETALHLAARYSRSDAAKRLLEA
SADANIQDNMGRTPLHAAVSADAQGVFQILIRNRATDLDARMHDGTTPLI
LAARLAVEGMLEDLINSHADVNAVDDLGKSALHWAAAVNNVDAAVVLLKN
GANKDMQNNREETPLFLAAREGSYETAKVLLDHFANRDITDHMDRLPRDI
AQERMHHDIVRLLDEYNLVRSPQLHGAPLGGTPTLSPPLCSPNGYLGSLK
PGVQGKKVRKPSSKGLACGSKEAKDLKARRKKSQDGKGCLLDSSGMLSPV
DSLESPHGYLSDVASPPLLPSPFQQSPSVPLNHLPGMPDTHLGIGHLNVA
AKPEMAALGGGGRLAFETGPPRLSHLPVASGTSTVLGSSSGGALNFTVGG
STSLNGQCEWLSRLQSGMVPNQYNPLRGSVAPGPLSTQAPSLQHGMVGPL
HSSLAASALSQMMSYQGLPSTRLATQPHLVQTQQVQPQNLQMQQQNLQPA
NIQQQQSLQPPPPPPQPHLGVSSAASGHLGRSFLSGEPSQADVQPLGPSS
LAVHTILPQESPALPTSLPSSLVPPVTAAQFLTPPSQHSYSSPVDNTPSH
QLQVPEHPFLTPSPESPDQWSSSSPHSNVSDWSEGVSSPPTSMQSQIARI
PEAFK.

An anti-inflammatory polypeptide can be identified based on its ability to bind to the calcium-binding site on Notch1 and/or interfere with or block the ability of Notch1 to bind to calcium. For example, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human Notch1 (SEQ ID NO: 369) selected from the group consisting of Phe-1520, Gln-1523, Arg-1524, Glu-1526, Ala-1553, Glu-1556, Trp-1557, Cys-1562, His-1602, Arg-1684, Gln-1685, Cys-1686, Ser-1691, Cys-1693, Phe-1694, and Phe-1703, or the equivalent amino acid residue(s) in a Notch1 protein of another species. Alternatively, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human Notch1 (SEQ ID NO: 369) selected from the group consisting of Phe-1520, Trp-1557, Cys-1562, and Phe-1703, or the equivalent amino acid residue(s) in a Notch1 protein of another species.

In certain embodiments, a polypeptide of the invention binds to human Notch1 (SEQ ID NO: 369) with an affinity of at least −650 kcal/mol, and in certain embodiments at least −700, −750, −800, −850, −900, −925, −950, −975, −1000, −1025, −1050, −1075 kcal/mol, or greater. The requisite binding affinity can correspond to a binding affinity that can be detected in vitro or in vivo. Alternatively, the requisite binding affinity can correspond to a binding affinity that can be detected in silico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatory polypeptides and Wnt8R, any Wnt8R protein sequence can be used. The Wnt8R sequence used for modeling generally folds into a functional Wnt8R protein or a Wnt8-binding fragment thereof. The Wnt8R protein sequence used for modeling can be selected based on the type of subject that the anti-inflammatory polypeptide is intended to treat (e.g., a human Wnt8R is selected if the intended subject is a human, a bovine Wnt8R is selected if the intended subject is a cow, etc.). The sequence used for modeling can be, for example, the bovine Wnt8R sequence (NCBI Acc. No. XP_005214377.1), which is as follows:


(SEQ ID NO: 370)
MEWGYLLEVTSLLAALALLQRSSGAAAASAKELACQEITVPLCKGIGYNY
TYMPNQFNHDTQDEAGLEVHQFWPLVEIQCSPDLKFFLCSMYTPICLEDY
KKPLPPCRSVCERAKAGCAPLMRQYGFAWPDRMRCDRLPEQGNPDTLCMD
YNRTDLTTAASSVDGDPVAGICYVGNQSLDNLLGFVLAPLVIYLFIGTMF
LLAGFVSLFRIRSVIKQQGGPTKTHKLEKLMIRLGLFTVLYTVPAAVVVA
CLFYEQHNRPRWEATHNCPCLRDQPDQARRPDYAVFMLKYFMCLVVGITS
GVWVWSGKTLESWRALCTRCCWASKGAGAAGAGAAGGGPGGGGPGAGGGG
GPGAGGAGSLYSDVSTGLTWRSGTASSVSYPKQMPLSQV.

An anti-inflammatory polypeptide can be identified based on its ability to bind to a Wnt ligand-binding site on Wnt8R and/or interfere with or block the ability of Wnt8R to bind to a Wnt ligand (e.g., Wnt8). For example, the anti-inflammatory polypeptide can bind to at least one amino acid residue of bovine Wnt8R (SEQ ID NO: 370) selected from the group consisting of Tyr-52, Gln-56, Phe-57, Asn-58, Met-91, Tyr-100, Lys-101, Pro-103, Pro-105, Pro-106, Arg-137 and Asp-145, or the equivalent amino acid residue(s) in a Wnt8R protein of another species. Alternatively, the anti-inflammatory polypeptide can bind to at least one amino acid residue of bovine Wnt8R (SEQ ID NO: 370) selected from the group consisting of Tyr-52, Phe-57, Tyr-100, and Asp-145, or the equivalent amino acid residue(s) in a Wnt8R protein of another species.

In certain embodiments, a polypeptide of the invention binds to bovine Wnt8R (SEQ ID NO: 370) with an affinity of at least −600 kcal/mol, and in certain embodiments at least −650, −700, −750, −800, −850, −875, −900, −925, −950, −975 kcal/mol, or greater. The requisite binding affinity can correspond to a binding affinity that can be detected in vitro or in vivo. Alternatively, the requisite binding affinity can correspond to a binding affinity that can be detected in silico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatory polypeptides and TRAIL, any TRAIL protein sequence can be used. The TRAIL sequence used for modeling in certain embodiments folds into a function TRAIL protein or a functional fragment thereof. The TRAIL protein sequence used for modeling can be selected based on the type of subject that the anti-inflammatory polypeptide is intended to treat (e.g., a human TRAIL is selected if the intended subject is a human, a bovine TRAIL is selected if the intended subject is a cow, etc.). The sequence used for modeling can be the human TRAIL sequence (GenBank Acc. No. EAW78466.1), which is as follows:


(SEQ ID NO: 371)
KEKQQNISPLVRERGPQRVAAHITGTRGRSNTLSSPNSKNEKALGRKINS
WESSRSGHSFLSNLHLRNGELVIHEKGFYYIYSQTYFRFQEEIKENTKND
KQMVQYIYKYTSYPDPILLMKSARNSCWSKDAEYGLYSIYQGGIFELKEN
DRIFVSVTNEHLIDMDHEASFFGAFLVG.

An anti-inflammatory polypeptide can be identified, for example, based on its ability to bind to the receptor binding site on TRAIL and/or interfere with or block the ability of TRAIL to bind to its receptor. For example, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human TRAIL (SEQ ID NO: 371) selected from the group consisting of Arg-130, Arg-158, Ser-159, Gly-160, His-161, Phe-163, Tyr-189, Arg-189, Gln-193, Glu-195, Glu-236, Tyr-237, Leu-239, Asp-267, Asp-269, His-270, and Glu-271, or the equivalent amino acid residue(s) in a TRAIL protein of another species. Alternatively, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human TRAIL (SEQ ID NO: 371) selected from the group consisting of Ala-123, His-161, Ser-162, Phe-163, Tyr-183, Tyr-185, Tyr-243, His-270, Glu-271, Phe-274, Phe-278, Leu-279, and Val-280, or the equivalent amino acid residue(s) in a TRAIL protein of another species. In other alternatives, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human TRAIL (SEQ ID NO: 371) selected from the group consisting of Phe-163, Tyr-243, Glu-271, and Phe-278, or the equivalent amino acid residue(s) in a TRAIL protein of another species.

In certain embodiments, an anti-inflammatory polypeptide can bind to human TRAIL (SEQ ID NO: 371) with an affinity of at least −650 kcal/mol, and in certain embodiments at least −700, −750, −800, −850, −900, −925, −950, −975, −1000, −1025, −1050 kcal/mol, or greater. The requisite binding affinity can correspond to a binding affinity that can be detected in vitro or in vivo. Alternatively, the requisite binding affinity can correspond to a binding affinity that can be detected in silico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatory polypeptides and IL6R, any IL6R protein sequence can be used. The IL6R sequence used for modeling generally folds into a functional IL6R protein or a IL6-binding fragment thereof. The IL6R protein sequence used for modeling can be selected based on the type of subject that the anti-inflammatory polypeptide is intended to treat (e.g., a human IL6R is selected if the intended subject is a human, a bovine IL6R is selected if the intended subject is a cow, etc.). The sequence used for modeling can be the human IL6R sequence (NCBI Acc. No. NP_786943.1), which is as follows:


(SEQ ID NO: 372)
MLTLQTWLVQALFIFLTTESTGELLDPCGYISPESPVVQLHSNFTAVCVL
KEKCMDYFHVNANYIVWKTNHFTIPKEQYTIINRTASSVTFTDIASLNIQ
LTCNILTFGQLEQNVYGITIISGLPPEKPKNLSCIVNEGKKMRCEWDGGR
ETHLETNFTLKSEWATHKFADCKAKRDTPTSCTVDYSTVYFVNIEVWVEA
ENALGKVTSDHINFDPVYKVKPNPPHNLSVINSEELSSILKLTWTNPSIK
SVIILKYNIQYRTKDASTWSQIPPEDTASTRSSFTVQDLKPFTEYVFRIR
CMKEDGKGYWSDWSEEASGITYEDNIASF.

An anti-inflammatory polypeptide can be identified, for example, based on its ability to bind to the IL6-binding site on IL6R and/or interfere with or block the ability of IL6R to bind to its ligand, IL6. For example, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human IL6R (SEQ ID NO: 372) selected from the group consisting of Glu-163, Gly-164, Phe-168, Gln-190, Phe-229, Tyr-230, Phe-279 and Gln-281, or the equivalent amino acid residue(s) in a IL6R protein of another species. Alternatively, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human IL6R (SEQ ID NO: 372) selected from the group consisting of Leu-108, Glu-140, Pro-162, Phe-229, Tyr-230, and Phe-279, or the equivalent amino acid residue(s) in a IL6R protein of another species. In other alternatives, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human IL6R (SEQ ID NO: 372) selected from the group consisting of Glu-140, Phe-229, Tyr-230, Phe-279, or the equivalent amino acid residue(s) in a IL6R protein of another species.

In certain embodiments, an anti-inflammatory polypeptide can bind to human IL6R (SEQ ID NO: 372) with an affinity of at least −600 kcal/mol, and in certain embodiments at least −650, −700, −750, −800, −850, −900, −925, −950, −975, −1000, −1025, −1050 kcal/mol, or greater. The requisite binding affinity can correspond to a binding affinity that can be detected in vitro or in vivo. Alternatively, the requisite binding affinity can correspond to a binding affinity that can be detected in silico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatory polypeptides and IL10R, any appropriate IL10R protein sequence can be used. The IL10R sequence used for modeling generally folds into a functional IL10R protein or a IL10-binding fragment thereof. The IL10R protein sequence used for modeling can be selected based on the type of subject that the anti-inflammatory polypeptide is intended to treat (e.g., a human IL10R is selected if the intended subject is a human, a bovine IL10R is selected if the intended subject is a cow, etc.). The sequence used for modeling can be the human IL10R sequence (NCBI Acc. No. NP_001549.2), which is as follows:


(SEQ ID NO: 373)
MLPCLVVLLAALLSLRLGSDAHGTELPSPPSVWFEAEFFHHILHWTPIPN
QSESTCYEVALLRYGIESWNSISNCSQTLSYDLTAVTLDLYHSNGYRARV
RAVDGSRHSNWTVTNTRFSVDEVTLTVGSVNLEIHNGFILGKIQLPRPKM
APANDTYESIFSHFREYEIAIRKVPGNFTFTHKKVKHENFSLLTSGEVGE
FCVQVKPSVASRSNKGMWSKEECISLTRQYFTVTNVIIFFAFVLLLSGAL
AYCLALQLYVRRRKKLPSVLLFKKPSPFIFISQRPSPETQDTIHPLDEEA
FLKVSPELKNLDLHGSTDSGFGSTKPSLQTEEPQFLLPDPHPQADRTLGN
REPPVLGDSCSSGSSNSTDSGICLQEPSLSPSTGPTWEQQVGSNSRGQDD
SGIDLVQNSEGRAGDTQGGSALGHHSPPEPEVPGEEDPAAVAFQGYLRQT
RCAEEKATKTGCLEEESPLTDGLGPKFGRCLVDEAGLHPPALAKGYLKQD
PLEMTLASSGAPTGQWNQPTEEWSLLALSSCSDLGISDWSFAHDLAPLGC
VAAPGGLLGSFNSDLVTLPLISSLQSSE.

An anti-inflammatory polypeptide can be identified, for example, based on its ability to bind to the IL10-binding site on IL10R and/or interfere with or block the ability of IL10R to bind to its ligand, IL10. For example, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human IL10R (SEQ ID NO: 373) selected from the group consisting of Tyr-43, Ile-45, Glu-46, Asp-61, Asn-73, Arg-76, Asn-94, Arg-96. Phe-143, Ala-189, Ser-190, and Ser-191, or the equivalent amino acid residue(s) in a IL6R protein of another species. Alternatively, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human IL10R (SEQ ID NO: 373) selected from the group consisting of Leu-41, Arg-42, Tyr-43, Ile-45, Glu-46, Ser-47, Trp-48, Arg-76, and Arg-78, or the equivalent amino acid residue(s) in a IL10R protein of another species. In other alternatives, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human IL10R (SEQ ID NO: 373) selected from the group consisting of Tyr-43, Ile-45, Glu-46, Trp-48, or the equivalent amino acid residue(s) in a IL10R protein of another species.

In certain embodiments, an anti-inflammatory polypeptide can bind to human IL10R (SEQ ID NO: 373) with an affinity of at least −600 kcal/mol, and in certain embodiments at least −650, −700, −750, −775, −800, −825, −850, −875, −900 kcal/mol, or greater. The requisite binding affinity can correspond to a binding affinity that can be detected in vitro or in vivo. Alternatively, the requisite binding affinity can correspond to a binding affinity that can be detected in silico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatory polypeptides and EGFR, any EGFR protein sequence can be used. The EGFR sequence used for modeling generally folds into a functional EGFR protein or a ligand-binding fragment thereof. The EGFR protein sequence used for modeling can be selected based on the type of subject that the anti-inflammatory polypeptide is intended to treat (e.g., a human EGFR is selected if the intended subject is a human, a bovine EGFR is selected if the intended subject is a cow, etc.). Alternatively, the sequence used for modeling can be the drosophila EGFR sequence (GenBank Acc. No. AAR85273.1), which is as follows:


(SEQ ID NO: 374)
KICIGTKSRLSVPSNKEHHYRNLRDRYTNCTYVDGNLELTWLPNENLDLS
FLDNIREVTGYILISHVDVKKVVFPKLQIIRGRTLFSLSVEEEKYALFVT
YSKMYTLEIPDLRDVLNGQVGFHNNYNLCHMRTIQWSEIVSNGTDAYYNY
DFTAPERECPKCHESCTHGCWGEGPKNCQKFSKLTCSPQCAGGRCYGPKP
RECCHLFCAGGCTGPTQKDCIACKNFFDEGVCKEECPPMRKYNPTTYVLE
TNPEGKYAYGATCVKECPGHLLRDNGACVRSCPQDKMDKGGECVPCNGPC
PKTCPGVTVLHAGNIDSFRNCTVIDGNIRILDQTFSGFQDVYANYTMGPR
YIPLDPERLEVFSTVKEITGYLNIEGTHPQFRNLSYFRNLETIHGRQLME
SMFAALAIVKSSLYSLEMRNLKQISSGSWIQHNRDLCYVSNIRWPAIQKE
PEQKVWVNENLRADLCEKNGTICSDQCNEDGCWGAGTDQCLNCKNFNFNG
TCIADCGYISNAYKFDNRTCKICHPECRTCNGAGADHCQECVHVRDGQHC
VSECPKNKYNDRGVCRECHATCDGCTGPKDTIGIGACTTCNLAIINNDAT
VKRCLLKDDKCPDGYFWEYVHPQEQGSLKPLAGRAVCRKCHPLCELCTNY
GYHEQ.

An anti-inflammatory polypeptide can be identified, for example, based on its ability to bind to the ligand-binding site on EGFR and/or interfere with or block the ability of at least one ligand to bind to EGFR. For example, the anti-inflammatory polypeptide can bind to at least one amino acid residue of drosophila EGFR (SEQ ID NO: 374) selected from the group consisting of Leu-10, Thr-40, Trp-41, Asp-48, Phe-51, Leu-63, His-66, Asp-68, Leu-88, and Tyr-101, or the equivalent amino acid residue(s) in a EGFR protein of another species. Alternatively, the anti-inflammatory polypeptide can bind to at least one amino acid residue of drosophila EGFR (SEQ ID NO: 374) selected from the group consisting of Trp-41, Asp-48, Phe-51, Asp-68, and Tyr-101, or the equivalent amino acid residue(s) in a EGFR protein of another species.

In certain embodiments, an anti-inflammatory polypeptide can bind to drosophila EGFR (SEQ ID NO: 374) with an affinity of at least −650 kcal/mol, and in certain embodiments at least −700, −750, −800, −850, −900, −925, −950, −975, −1000, −1025, −1050 kcal/mol, or greater. The requisite binding affinity can correspond to a binding affinity that can be detected in vitro or in vivo. Alternatively, the requisite binding affinity can correspond to a binding affinity that can be detected in silico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatory polypeptides and CDK6, any CDK6 protein sequence can be used. The CDK6 sequence used for modeling generally folds into a functional CDK6 protein or a functional fragment thereof. The CDK6 protein sequence used for modeling can be selected based on the type of subject that the anti-inflammatory polypeptide is intended to treat (e.g., a human CDK6 is selected if the intended subject is a human, a bovine CDK6 is selected if the intended subject is a cow, etc.). The sequence used for modeling can be the human CDK6 sequence (NCBI Acc. No. NP_001250.1), which is as follows:


(SEQ ID NO: 375)
MEKDGLCRADQQYECVAEIGEGAYGKVFKARDLKNGGRFVALKRVRVQTG
EEGMPLSTIREVAVLRHLETFEHPNVVRLFDVCTVSRTDRETKLTLVFEH
VDQDLTTYLDKVPEPGVPTETIKDMMFQLLRGLDFLHSHRVVHRDLKPQN
ILVTSSGQIKLADFGLARIYSFQMALTSVVVTLWYRAPEVLLQSSYATPV
DLWSVGCIFAEMFRRKPLFRGSSDVDQLGKILDVIGLPGEEDWPRDVALP
RQAFHSKSAQPIEKFVTDIDELGKDLLLKCLTFNPAKRISAYSALSHPYF
QDLERCKENLDSHLPPSQNTSELNTA.

An anti-inflammatory polypeptide can be identified, for example, based on its ability to bind to the active site on CDK6 and/or interfere with or block the kinase activity of CDK6 or the ability of CDK6 to phosphorylate one or more CDK6 substrates. For example, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human CDK6 (SEQ ID NO: 375) selected from the group consisting of Val-142, Arg-144, Asp-145, Ser-171, Val-180, Val-181, Leu-183, Arg-186, Val-190, Gln-193, Tyr-196, and Val-200, or the equivalent amino acid residue(s) in a CDK6 protein of another species. Alternatively, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human CDK6 (SEQ ID NO: 375) selected from the group consisting of Asp-145, Val-180, and Tyr-196, or the equivalent amino acid residue(s) in a CDK6 protein of another species.

In certain embodiments, an anti-inflammatory polypeptide can bind to human CDK6 (SEQ ID NO: 375) with an affinity of at least −600 kcal/mol, and in certain embodiments at least −650, −700, −750, −800, −850, −900, −925, −950, −975, −1000, −1025, −1050 kcal/mol, or greater. The requisite binding affinity can correspond to a binding affinity that can be detected in vitro or in vivo. Alternatively, the requisite binding affinity can correspond to a binding affinity that can be detected in silico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatory polypeptides and histone methyl transferase (HMT), any HMT protein sequence can be used. The HMT sequence used for modeling generally folds into a functional HMT protein or a functional fragment thereof. The HMT protein sequence used for modeling can be selected based on the type of subject that the anti-inflammatory polypeptide is intended to treat (e.g., a human HMT is selected if the intended subject is a human, a bovine HMT is selected if the intended subject is a cow, etc.). The sequence used for modeling can be, for example, the Paramecium bursaria Chlorella virus 1 HMT sequence (NCBI Acc. No. NP_048968.1), which is as follows:


(SEQ ID NO: 376)
MFNDRVIVKKSPLGGYGVFARKSFEKGELVEECLCIVRHNDDWGTALEDY
LFSRKNMSAMALGFGAIFNHSKDPNARHELTAGLKRMRIFTIKPIAIGEE
ITISYGDDYWLSRPRLTQN.

An anti-inflammatory polypeptide can be identified, for example, based on its ability to bind to the active site on HMT and/or interfere with or block the methyl transferase activity of HMT or the ability of HMT to methylate histone substrates. For example, the anti-inflammatory polypeptide can bind to at least one amino acid residue of Paramecium bursaria HMT (SEQ ID NO: 376) selected from the group consisting of Asn-69, His-70, Ser-71, Lys-72, Asp-73, Pro-74, and Asn-75, or the equivalent amino acid residue(s) in a HMT protein of another species. Alternatively, the anti-inflammatory polypeptide can bind to at least one amino acid residue of Paramecium bursaria HMT (SEQ ID NO: 376) selected from the group consisting of Tyr-16, Glu-48, Tyr-50, Leu-51, Phe-52, and Asn-69, or the equivalent amino acid residue(s) in a HMT protein of another species.

In certain embodiments, an anti-inflammatory polypeptide can bind to Paramecium bursaria HMT (SEQ ID NO: 376) with an affinity of at least −600 kcal/mol, and in certain embodiments at least −650, −700, −750, −800, −850, −900, −925, −950, −975, −1000, −1025, −1050 kcal/mol, or greater. The requisite binding affinity can correspond to a binding affinity that can be detected in vitro or in vivo. Alternatively, the requisite binding affinity can correspond to a binding affinity that can be detected in silico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatory polypeptides and CD47, any CD47 protein sequence can be used. The CD47 sequence used for modeling generally folds into a functional CD47 protein or a SIRP-α-binding portion thereof. The CD47 protein sequence used for modeling can be selected based on the type of subject that the anti-inflammatory polypeptide is intended to treat (e.g., a human CD47 is selected if the intended subject is a human, a bovine CD47 is selected if the intended subject is a cow, etc.). The sequence used for modeling can be the human CD47 sequence (NCBI Acc. No. XP_005247966.1), which is as follows:


(SEQ ID NO: 377)
MWPLVAALLLGSACCGSAQLLFNKTKSVEFTFCNDTVVIPCFVTNMEAQN
TTEVYVKWKFKGRDIYTFDGALNKSTVPTDFSSAKIEVSQLLKGDASLKM
DKSDAVSHTGNYTCEVTELTREGETIIELKYRVVSWFSPNENILIVIFPI
FAILLFWGQFGIKTLKYRSGGMDEKTIALLVAGLVITVIVIVGAILFVPG
EYSLKNATGLGLIVTSTGILILLHYYVFSTAIGLTSFVIAILVIQVIAYI
LAVVGLSLCIAACIPMHGPLLISGLSILALAQLLGLVYMKFVE.

An anti-inflammatory polypeptide can be identified, for example, based on its ability to bind to the SIRP-α-binding site on HMT and/or interfere with or block the binding of CD47 to SIRP-α. For example, the anti-inflammatory polypeptide can bind to at least one amino acid residue of CD47 (SEQ ID NO: 377) selected from the group consisting of Glu-29. Ala-30, Glu-35, Val-36, Tyr-37, Lys-39, Thr-49, Asp-51, Glu-97, Thr-99, Leu-101, Thr-102, Arg-103, Glu-104, and Glu-106, or the equivalent amino acid residue(s) in a CD47 protein of another species. In certain embodiments, the anti-inflammatory polypeptide can bind to at least one amino acid residue of CD47 (SEQ ID NO: 377) selected from the group consisting of Glu-29, Glu-35, Lys-39, Glu-97, Leu-101, Thr-102, Arg-103, Glu-104, and Glu-106, or the equivalent amino acid residue(s) in a CD47 protein of another species. Alternatively, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human CD47 (SEQ ID NO: 377) selected from the group consisting of Tyr-16, Glu-48, Tyr-50, Leu-51, Phe-52, and Asn-6 Tyr-37, Thr-49, Phe-50, Asp-51, Ala-53, Glu-97, Val-98, Glu-100, Leu-101, Thr-102, Glu-104, Glu-106, Gly-107, or the equivalent amino acid residue(s) in a CD47 protein of another species. In certain embodiments, the anti-inflammatory polypeptide can bind to at least one amino acid residue of CD47 (SEQ ID NO: 377) selected from the group consisting of Tyr-37, Glu-97, Glu-100, Leu-101, Glu-104, Glu-106, or the equivalent amino acid residue(s) in a CD47 protein of another species.

In certain embodiments, an anti-inflammatory polypeptide can bind to human CD47 (SEQ ID NO: 377) with an affinity of at least −550 kcal/mol, and in certain embodiments at least −600, −650, −675, −700, −725, −750, −775, −800 kcal/mol, or greater. The requisite binding affinity can correspond to a binding affinity that can be detected in vitro or in vivo. Alternatively, the requisite binding affinity can correspond to a binding affinity that can be detected in silico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatory polypeptides and SIRP-α, any SIRP-α protein sequence can be used. The SIRP-α sequence used for modeling generally folds into a functional SIRP-α protein or a CD47-binding fragment thereof. The SIRP-α protein sequence used for modeling can be selected based on the type of subject that the anti-inflammatory polypeptide is intended to treat (e.g., a human SIRP-α is selected if the intended subject is a human, a bovine SIRP-α is selected if the intended subject is a cow, etc.). The sequence used for modeling can be the human SIRP-α sequence (GenBank Acc. No. AAH26692.1), which is as follows:


(SEQ ID NO: 378)
MEPAGPAPGRLGPLLCLLLAASCAWSGVAGEEELQVITQPDKSVSVAAGE
SAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKR
ENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPSA
PVVSGPAARATPQHTVSFTCESHGFSPRDITLKWFKNGNELSDFQTNVDP
VGESVSYSIHSTAKVVLTREDVHSQVICEVAHVTLQGDPLRGTANLSETI
RVPPTLEVTQQPVRAENQVNVTCQVRKFYPQRLQLTWLENGNVSRTETAS
TVTENKDGTYNWMSWLLVNVSAHRDDVKLTCQVEHDGQPAVSKSHDLKVS
AHPKEQGSNTAAENTGSNERNIYIVVGVVCTLLVALLMAALYLVRIRQKK
AQGSTSSTRLHEPEKNAREITQVQSLDTNDITYADLNLPKGKKPAPQAAE
PNNHTEYASIQTSPQPASEDTLTYADLDMVHLNRTPKQPAPKPEPSFSEY
ASVQVPRK.

An anti-inflammatory polypeptide can be identified, for example, based on its ability to bind to the HMT-binding site on SIRP-α and/or interfere with or block the binding of SIRP-α to HMT. For example, the anti-inflammatory polypeptide can bind to at least one amino acid residue of SIRP-α (SEQ ID NO: 378) selected from the group consisting of Leu-30, Gln-37, Gln-52, Lys-53, Ser-66, Thr-67, Arg-69, Met-72, Phe-74, Lys-96 and Asp-100, or the equivalent amino acid residue(s) in a SIRP-α protein of another species. Alternatively, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human SIRP-α (SEQ ID NO: 378) selected from the group consisting of Tyr-50, Gln-52, Pro-58, Ser-66, Thr-67, and Ser-77, or the equivalent amino acid residue(s) in a SIRP-α protein of another species. In certain embodiments, the anti-inflammatory polypeptide can bind to at least one amino acid residue of SIRP-α (SEQ ID NO: 378) selected from the group consisting of Tyr-50, Gln-52, Ser-66, and Thr-67, or the equivalent amino acid residue(s) in a SIRP-α protein of another species.

In certain embodiments, an anti-inflammatory polypeptide can bind to human SIRP-α (SEQ ID NO: 378) with an affinity of at least −600 kcal/mol, and in certain embodiments at least −650, −700, −750, −800, −825, −850, −875, −900, −925, −950, −975, −1000 kcal/mol, or greater. The requisite binding affinity can correspond to a binding affinity that can be detected in vitro or in vivo. Alternatively, the requisite binding affinity can correspond to a binding affinity that can be detected in silico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatory polypeptides and CD206, any CD206 protein sequence can be used. The CD206 sequence used for modeling generally folds into a functional CD206 protein or a mannose-binding fragment thereof. The CD206 protein sequence used for modeling can be selected based on the type of subject that the anti-inflammatory polypeptide is intended to treat (e.g., a human CD206 is selected if the intended subject is a human, a bovine CD206 is selected if the intended subject is a cow, etc.). The sequence used for modeling can be the human CD206 sequence (NCBI Acc. No. NP_002429.1), which is as follows:


(SEQ ID NO: 379)
MRLPLLLVFASVIPGAVLLLDTRQFLIYNEDHKRCVDAVSPSAVQTAACN
QDAESQKFRWVSESQIMSVAFKLCLGVPSKTDWVAITLYACDSKSEFQKW
ECKNDTLLGIKGEDLFFNYGNRQEKNIMLYKGSGLWSRWKIYGTTDNLCS
RGYEAMYTLLGNANGATCAFPFKFENKWYADCTSAGRSDGWLWCGTTTDY
DTDKLFGYCPLKFEGSESLWNKDPLTSVSYQINSKSALTWHQARKSCQQQ
NAELLSITEIHEQTYLTGLTSSLTSGLWIGLNSLSFNSGWQWSDRSPFRY
LNWLPGSPSAEPGKSCVSLNPGKNAKWENLECVQKLGYICKKGNTTLNSF
VIPSESDVPTHCPSQWWPYAGHCYKIHRDEKKIQRDALTTCRKEGGDLTS
IHTIEELDFIISQLGYEPNDELWIGLNDIKIQMYFEWSDGTPVTFTKWLR
GEPSHENNRQEDCVVMKGKDGYWADRGCEWPLGYICKMKSRSQGPEIVEV
EKGCRKGWKKHHFYCYMIGHTLSTFAEANQTCNNENAYLTTIEDRYEQAF
LTSFVGLRPEKYFWTGLSDIQTKGTFQWTIEEEVRFTHWNSDMPGRKPGC
VAMRTGIAGGLWDVLKCDEKAKFVCKHWAEGVTHPPKPTTTPEPKCPEDW
GASSRTSLCFKLYAKGKHEKKTWFESRDFCRALGGDLASINNKEEQQTIW
RLITASGSYHKLFWLGLTYGSPSEGFTWSDGSPVSYENWAYGEPNNYQNV
EYCGELKGDPTMSWNDINCEHLNNWICQIQKGQTPKPEPTPAPQDNPPVT
EDGWVIYKDYQYYFSKEKETMDNARAFCKRNFGDLVSIQSESEKKFLWKY
VNRNDAQSAYFIGLLISLDKKFAWMDGSKVDYVSWATGEPNFANEDENCV
TMYSNSGFWNDINCGYPNAFICQRHNSSINATTVMPTMPSVPSGCKEGWN
FYSNKCFKTFGFMEEERKNWQEARKACIGFGGNLVSIQNEKEQAFLTYHM
KDSTFSAWTGLNDVNSEHTFLWTDGRGVHYTNWGKGYPGGRRSSLSYEDA
DCVVIIGGASNEAGKWMDDTCDSKRGYICQTRSDPSLTNPPATIQTDGFV
KYGKSSYSLMRQKFQWHEAETYCKLHNSLIASILDPYSNAFAWLQMETSN
ERVWIALNSNLTDNQYTWTDKWRVRYTNWAADEPKLKSACVYLDLDGYWK
TAHCNESFYFLCKRSDEIPATEPPQLPGRCPESDHTAWIPFHGHCYYIES
SYTRNWGQASLECLRMGSSLVSIESAAESSFLSYRVEPLKSKTNFWIGLF
RNVEGTWLWINNSPVSFVNWNTGDPSGERNDCVALHASSGFWSNIHCSSY
KGYICKRPKIIDAKPTHELLTTKADTRKMDPSKPSSNVAGVVIIVILLIL
TGAGLAAYFFYKKRRVHLPQEGAFENTLYFNSQSSPGTSDMKDLVGNIEQ
NEHSVI.

An anti-inflammatory polypeptide can be identified, for example, based on its ability to bind to the mannose-binding site on CD206 and/or interfere with or block the binding of SIRP-mannose to CD206. For example, the anti-inflammatory polypeptide can bind to at least one amino acid residue of CD206 (SEQ ID NO: 379) selected from the group consisting of Glu-725, Tyr-729, Glu-733, Asn-747, and Asp-748, or the equivalent amino acid residue(s) in a CD206 protein of another species. Alternatively, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human CD206 (SEQ ID NO: 379) selected from the group consisting of Phe-708, Thr-709, Trp-710, Pro-714, Glu-719, Asn-720, Trp-721, Ala-722, Glu-725, Tyr-729, Glu-733, Asn-747, Asp-748, Ser-1691, Cys-1693, Phe-1694, and Phe-1703, or the equivalent amino acid residue(s) in a CD206 protein of another species. In certain embodiments, the anti-inflammatory polypeptide can bind to at least one amino acid residue of CD206 (SEQ ID NO: 379) selected from the group consisting of Phe-708, Trp-710, Trp-721, Glu-725, Tyr-729, Glu-733, or the equivalent amino acid residue(s) in a CD206 protein of another species.

In certain embodiments, an anti-inflammatory polypeptide can bind to human CD206 (SEQ ID NO: 379) with an affinity of at least −650 kcal/mol, and in certain embodiments at least −700, −750, −800, −850, −900, −925, −950, −975, −1000, −1025, −1050 kcal/mol, or greater. The requisite binding affinity can correspond to a binding affinity that can be detected in vitro or in vivo. Alternatively, the requisite binding affinity can correspond to a binding affinity that can be detected in silico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatory polypeptides and TGM2, any TGM2 protein sequence can be used. The TGM2 sequence used for modeling generally folds into a functional TGM2 protein or acyl-transferase catalytic fragment thereof. The TGM2 protein sequence used for modeling can be selected based on the type of subject that the anti-inflammatory polypeptide is intended to treat (e.g., a human TGM2 is selected if the intended subject is a human, a bovine TGM2 is selected if the intended subject is a cow, etc.). The sequence used for modeling can be the human TGM2 sequence (GenBank Acc. No. AAB95430.1), which is as follows:


(SEQ ID NO: 380)
MMDASKELQVLHIDFLNQDNAVSHHTWEFQTSSPVFRRGQVFHLRLVLNQ
PLQSYHQLKLEFSTGPNPSIAKHTLWLDPRTPSDHYNWQATLQNESGKEV
TVAVTSSPNAILGKYQLNVKTGNHILKSEENILYLLFNPWCKEDMVFMPD
EDERKEYILNDTGCHYVGAARSIKCKPWNFGQFEKNVLDCCISLLTESSL
KPTDRRDPVLVCRAMCAMMSFEKGQGVLIGNWTGDYEGGTAPYKWTGSAP
ILQQYYNTKQAVCFGQCWVFAGILTTVLRALGIPARSVTGFDSAHDTERN
LTVDTYVNENGEKITSMTHDSVWNFHVWTDAWMKRPDLPKGYDGWQAVDA
TPQERSQGVFCCGPSPLTAIRKGDIFIVYDTRFVFSEVNGDRLIWLVKMV
NGQEELHVISMETTSIGKNISTKAVGQDRRRDITYEYKYPEGSSEERQVM
DHAFLLLSSEREHRRPVKENFLHMSVQSDDVLLGNSVNFTVILKRKTAAL
QNVNILGSFELQLYTGKKMAKLCDLNKTSQIQGQVSEVTLTLDSKTYINS
LAILDDEPVIRGFIIAEIVESKEIMASEVFTSFQYPEFSIELPNTGRIGQ
LLVCNCIFKNTLAIPLTDVKFSLESLGISSLQTSDHGTVQPGETIQSQIK
CTPIKTGPKKFIVKLSSKQVKEINAQKIVLITK.

An anti-inflammatory polypeptide can be identified, for example, based on its ability to bind to the active site on TGM2 and/or interfere with or block the acyl-transferase activity of TGM2. For example, the anti-inflammatory polypeptide can bind to at least one amino acid residue of TGM2 (SEQ ID NO: 380) selected from the group consisting of Cys-277, His-335, and Asp-358, or the equivalent amino acid residue(s) in a TGM2 protein of another species.

In certain embodiments, an anti-inflammatory polypeptide can bind to human TGM2 (SEQ ID NO: 380) with an affinity of at least −650 kcal/mol, and in certain embodiments at least −700, −750, −800, −850, −900, −925, −950, −975, −1000, −1025, −1050 kcal/mol, or greater. The requisite binding affinity can correspond to a binding affinity that can be detected in vitro or in vivo. Alternatively, the requisite binding affinity can correspond to a binding affinity that can be detected in silico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatory polypeptides and serum albumin, any serum albumin protein sequence can be used. The serum albumin sequence used for modeling generally folds into a functional serum albumin protein or a functional fragment thereof. The serum albumin protein sequence used for modeling can be selected based on the type of subject that the anti-inflammatory polypeptide is intended to treat (e.g., a human serum albumin (HSA) is selected if the intended subject is a human, a bovine serum albumin (BSA) is selected if the intended subject is a cow, etc.). The sequence used for modeling can be the human serum albumin (HSA) sequence (NCBI Acc. No. NP_000468.1), which is as follows:


(SEQ ID NO: 381)
DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFA
KTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNE
CFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFY
APELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKC
ASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDL
LECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPA
DLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLA
KTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGE
YKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAE
DYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPK
EFNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDD
FAAFVEKCCKADDKETCFAEEGKKLVAASQAALGL.

An anti-inflammatory polypeptide can be identified, for example, based on its ability to bind to HSA under physiological conditions (e.g., in the blood stream).

In certain embodiments, an anti-inflammatory polypeptide can bind to HSA (SEQ ID NO: 381) with an affinity of at least −650 kcal/mol, and in certain embodiments at least −700, −750, −800, −850, −900, −925, −950, −975, −1000, −1025, −1050 kcal/mol, or greater. The requisite binding affinity can correspond to a binding affinity that can be detected in vitro or in vivo. Alternatively, the requisite binding affinity can correspond to a binding affinity that can be detected in silico, e.g., using the ClusPro™ algorithm.

In certain embodiments, an anti-inflammatory polypeptide binds to two or more targets (e.g., pro-inflammatory targets). In some embodiments, an anti-inflammatory polypeptide binds to three, four, five, or more pro-inflammatory targets. For example, an anti-inflammatory polypeptide can bind to any combination of targets disclosed herein. Such binding can be based on in silico, in vitro, or in vivo data. Thus, an anti-inflammatory polypeptide can bind to two or more NF-kB Class II subunits (e.g., RelB and at least one other NF-kB Class II subunit, such as RelA, cRel, NF-kB1, or NF-kB2). Alternatively (or in addition), an anti-inflammatory polypeptide can bind to an NF-kB Class II subunit (e.g., RelB) and at least one other signaling molecule (e.g., at least one signaling molecule selected from the group consisting of TGFβ, Notch1, Wnt8R, TRAIL, IL6R, IL10R, EGFR, CDK6, CD206, CD47, SIRP-α, HMT, and TGM2). For example, an anti-inflammatory polypeptide can bind to an NF-kB Class II subunit (e.g., RelB) and at least one signaling molecule selected from the group consisting of TGFβ, Notch1, Wnt8R, TRAIL, IL6R, IL10R, EGFR, and CDK6. Alternatively, an anti-inflammatory polypeptide can bind to an NF-kB Class II subunit (e.g., RelB) and at least one signaling molecule selected from the group consisting of CD206, CD47, SIRP-α, and TGM2. In other alternatives, an anti-inflammatory polypeptide can bind to an NF-kB Class II subunit (e.g., RelB) and HMT. In other alternatives, an anti-inflammatory polypeptide can bind to at least one signaling molecule selected from the group consisting of TGFβ, Notch1, Wnt8R, TRAIL, IL6R, IL10R, EGFR, and CDK6, and at least one signaling molecule selected from the group consisting of CD206, CD47, SIRP-α, and TGM2. In other alternatives, an anti-inflammatory polypeptide can bind to at least one signaling molecule selected from the group consisting of TGFβ, Notch1, Wnt8R, TRAIL, IL6R, IL10R, EGFR, and CDK6, and also bind to HMT. In still other embodiments, an anti-inflammatory polypeptide can bind to an NF-kB Class II subunit (e.g., RelB), at least one signaling molecule selected from the group consisting of TGFβ, Notch1, Wnt8R, TRAIL, IL6R, IL10R, EGFR, and CDK6, at least one signaling molecule selected from the group consisting of CD206, CD47, SIRP-α, and TGM2, and also HMT. In certain embodiments, an anti-inflammatory polypeptide binds to two or more pro-inflammatory targets and also serum albumin (e.g., human serum albumin).

For modeling interactions between potential anti-inflammatory polypeptides and LEGUMAIN, any LEGUMAIN protein sequence can be used. The LEGUMAIN sequence used for modeling generally folds into a functional LEGUMAIN protein or a functional fragment thereof. The LEGUMAIN protein sequence used for modeling can be selected based on the type of subject that the anti-inflammatory polypeptide is intended to treat (e.g., a human LEGUMAIN is selected if the intended subject is a human, a bovine LEGUMAIN is selected if the intended subject is a cow, etc.). The sequence used for modeling can be the human LEGUMAIN sequence (GenBank Acc. No. AAH03061.1).


(SEQ ID NO: 137)
IVVMMYDDIAYSEDNPTPGIVINRPNGTDVYQGVPKDYTGEDVTPQNFLAVLRGDAEAVKGIGSG
HTNTSHVMQYGNKTISTMKVMQFQGMKRKASSPVPLPPVTHLDLTPSPDVPLTIMKRKLMNTNDL
EESRQLTEEIQRHLDARHLIEKSVRKIVSLLAASEAEVEQLLSERAPLTGHSCYPEALLHFRTHC
FNWHSPTYEYALRHLYVLVNLCEKPYPLHRIKLSMDHVCLGHY.

An anti-inflammatory polypeptide can be identified, for example, based on its ability to bind to the active site on LEGUMAIN and/or interfere with or block the ability of LEGUMAIN to bind to its target. For example, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human LEGUMAIN (SEQ ID NO: 137) selected from the group consisting of Asn-44, Arg-46, His-159, Glu-189, Cys-191, Ser-217, Ser-218 and Asp-233, or the equivalent amino acid residue(s) in a LEGUMAIN protein of another species. Alternatively, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human LEGUMAIN (SEQ ID NO: 137) selected from the group consisting of Asn-44, Glu-189 and Asp-233, or the equivalent amino acid residue(s) in a LEGUMAIN protein of another species.

In certain embodiments, an anti-inflammatory polypeptide can bind to human LEGUMAIN (SEQ ID NO: 137) with an affinity of at least −600 kcal/mol, and in certain embodiments at least −650, −700, −750, −800, −850, −900, −925, −950 kcal/mol, or greater. The requisite binding affinity can correspond to a binding affinity that can be detected in vitro or in vivo. Alternatively, the requisite binding affinity can correspond to a binding affinity that can be detected in silico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatory polypeptides and CD209, any CD209 protein sequence can be used. The CD209 sequence used for modeling generally folds into a functional CD209 protein or a functional fragment thereof. The CD209 protein sequence used for modeling can be selected based on the type of subject that the anti-inflammatory polypeptide is intended to treat (e.g., a human CD209 is selected if the intended subject is a human, a bovine CD209 is selected if the intended subject is a cow, etc.). The sequence used for modeling can be the human CD209 sequence (GenBank Acc. No. NP_001138366.1).


(SEQ ID NO: 140)
MSDSKEPRLQQLGLLVSKVPSSISQEQSRQDAIYQKLTQLKAAVGELSEKSKLQEIYQELTQLKA
AVGELPEKSKLQEIYQELTRLKAAVGELPEKSKLQEIYQELTWLKAAVGELPEKSKMQEIYQELT
RLKAAVGELPEKSKQQEIYQELTRLKAAVGELPEKSKQQEIYQELTRLKAAVGELPEKSKQQEIY
QELTQLKAAVERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQLVVIKSAEEQNFLQ
NLAKFWICKKSAASCSRDEEQFLSPAPATPNPPPA

An anti-inflammatory polypeptide can be identified, for example, based on its ability to bind to the active site on CD209 and/or interfere with or block the ability of CD209 to bind to its receptor. For example, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human CD209 (SEQ ID NO: 140) selected from the group consisting of Phe-269, Glu-280, Glu-303, Asn-305, Asn-306, Glu-310, Asp-311, Ser-316, Gly-317, Asn-321 and Lys-324 or the equivalent amino acid residue(s) in a CD209 protein of another species. Alternatively, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human CD209 (SEQ ID NO: 140) selected from the group consisting of Phe-269, Glu-280, Glu-303, Glu-310, Asp-311, Asn-321 and Lys-324, or the equivalent amino acid residue(s) in a CD209 protein of another species.

In certain embodiments, an anti-inflammatory polypeptide can bind to human CD209 (SEQ ID NO: 140) with an affinity of at least −600 kcal/mol, and in certain embodiments at least −650, −700, −750, −800, −850, −900, −925, −950, −1,000, −1,050 kcal/mol, or greater. The requisite binding affinity can correspond to a binding affinity that can be detected in vitro or in vivo. Alternatively, the requisite binding affinity can correspond to a binding affinity that can be detected in silico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatory polypeptides and FAS, any FAS protein sequence can be used. The FAS sequence used for modeling generally folds into a functional FAS protein or a functional fragment thereof. The FAS protein sequence used for modeling can be selected based on the type of subject that the anti-inflammatory polypeptide is intended to treat (e.g., a human FAS is selected if the intended subject is a human, a bovine FAS is selected if the intended subject is a cow, etc.). The sequence used for modeling can be the human FAS sequence (NCBI Reference Sequence: NP_000034.1).


(SEQ ID NO: 152)
MLGIWTLLPLVLTSVARLSSKSVNAQVTDINSKGLELRKTVTTVETQNLEGLHHDGQFCHKPCPP
GERKARDCTVNGDEPDCVPCQEGKEYTDKAHFSSKCRRCRLCDEGHGLEVEINCTRTQNTKCRCK
PNFFCNSTVCEHCDPCTKCEHGIIKECTLTSNTKCKEEGSRSNLGWLCLLLLPIPLIVWVKRKEV
NFRNEIQSLV.

An anti-inflammatory polypeptide can be identified, for example, based on its ability to bind to the active site on FAS and/or interfere with or block the ability of FAS to bind to its ligand. For example, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human FAS (SEQ ID NO: 152) selected from the group consisting of Lys-251, Lys-296, Lys-299. Leu-303, Leu-306, Ala-307, Glu-308, Lys-309, Gln-311. Ile-314, Leu-315, Asp-317, Ile-318 and Thr-319, or the equivalent amino acid residue(s) in a FAS protein of another species. Alternatively, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human FAS (SEQ ID NO: 152) selected from the group consisting of Lys-296, Lys-299, Leu-306, Ala-307, Glu-308, Ile-314, Leu-315, Asp-317 and Ile-318, or the equivalent amino acid residue(s) in a FAS protein of another species.

In certain embodiments, an anti-inflammatory polypeptide can bind to human FAS (SEQ ID NO: 152) with an affinity of at least −600 kcal/mol, and in certain embodiments at least −650, −700, −750, −800, −850, −900, −925, −950 kcal/mol, or greater. The requisite binding affinity can correspond to a binding affinity that can be detected in vitro or in vivo. Alternatively, the requisite binding affinity can correspond to a binding affinity that can be detected in silico, e.g., using the ClusPro™ algorithm.

Programmed cell death protein 1, also known as PD-1 and CD279 (cluster of differentiation 279), is a protein that in humans is encoded by the PDCD1 gene. PD-1 is a cell surface receptor that belongs to the immunoglobulin superfamily and is expressed on T cells and pro-B cells. PD-1 binds two ligands, PD-L1 and PD-L2, PD-1, functioning as an immune checkpoint plays an important role in down regulating the immune system by preventing the activation of T-cells, which in turn reduces autoimmunity and promotes self-tolerance. The inhibitory effect of PD-1 is accomplished through a dual mechanism of promoting apoptosis (programmed cell death) in antigen specific T-cells in lymph nodes while simultaneously reducing apoptosis in regulatory T cells (suppressor T cells).

For modeling interactions between potential anti-inflammatory polypeptides and PD-1, any PD-1 protein sequence can be used. The PD-1 sequence used for modeling generally folds into a functional PD-1 protein or a functional fragment thereof. The PD-1 protein sequence used for modeling can be selected based on the type of subject that the anti-inflammatory polypeptide is intended to treat (e.g., a human PD-1 is selected if the intended subject is a human, a bovine PD-1 is selected if the intended subject is a cow, etc.). The sequence used for modeling can be the human PD-1 sequence (Locus: XP_006712636.1).


(SEQ ID NO: 159)
KAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQFQTLVVGVVGGLLGSLVLLVWVLAVICSRA
ARG.

An anti-inflammatory polypeptide can be identified, for example, based on its ability to bind to the active site on PD-1 and/or interfere with or block the ability of PD-1 to bind to its receptor. For example, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human PD-1 (SEQ ID NO: 159) selected from the group consisting of Val-64. Asn-66, Tyr-68, Met-70, Thr-76, Lys-78, Thr-120, Leu-122, Ala-125, Ser-127, or the equivalent amino acid residue(s) in a PD-1 protein of another species. Alternatively, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human PD-1 (SEQ ID NO: 159) selected from the group consisting of Tyr-68, Met-70, Lys-78 and Leu-122, or the equivalent amino acid residue(s) in a PD-1 protein of another species.

In certain embodiments, an anti-inflammatory polypeptide can bind to human PD-1 (SEQ ID NO: 159) with an affinity of at least −600 kcal/mol, and in certain embodiments at least −650, −700, −750, −800, −850, −900, −925, −950, −1,000 kcal/mol, or greater. The requisite binding affinity can correspond to a binding affinity that can be detected in vitro or in vivo. Alternatively, the requisite binding affinity can correspond to a binding affinity that can be detected in silico, e.g., using the ClusPro™ algorithm.

Dual specificity mitogen-activated protein kinase kinase 7, also known as MAP kinase kinase 7 or MKK7, is an enzyme that in humans is encoded by the MAP2K7 gene. This protein is a member of the mitogen-activated protein kinase kinase family. The MKK7 protein exists as six different isoforms with three possible N-termini (α, β, and γ isoforms) and two possible C-termini (1 and 2 isoforms). MKK7 is involved in signal transduction mediating the cell responses to proinflammatory cytokines, and environmental stresses. This kinase specifically activates MAPK8/JNK1 and MAPK9/JNK2, and this kinase itself is phosphorylated and activated by MAP kinase kinase kinases including MAP3K1/MEKK1, MAP3K2/MEKK2, MAP3K3/MEKK5, and MAP4K2/GCK.

For modeling interactions between potential anti-inflammatory polypeptides and MKK7, any MKK7 protein sequence can be used. The MKK7 sequence used for modeling generally folds into a functional MKK7 protein or a functional fragment thereof. The MKK7 protein sequence used for modeling can be selected based on the type of subject that the anti-inflammatory polypeptide is intended to treat (e.g., a human MKK7 is selected if the intended subject is a human, a bovine MKK7 is selected if the intended subject is a cow, etc.). The sequence used for modeling can be the human MKK7 sequence (NCBI Reference Sequence: NP_001284484.1).


(SEQ ID NO: 166)
MAASSLEQKLSRLEAKLKQENREARRRIDLNLDISPQRPRPIIVITTSPAPAPSQRAALQLPLAN
DGGSRSPSSESSPQHPTPPARPRHMLGLPSTLFTPRSMESIEIDQKLQEIMKQTGYLTIGGQRYQ
ISLVELATGQFPYKNCKTDFEVLTKVLQEEPPLLPGHMGFSGDFQSFVKDCLTKDHRKRPKYNKL
LEHSFIKRYETLEVDVASWFKDVMAKTESPRTSGVLSQPHLPFFR.

An anti-inflammatory polypeptide can be identified, for example, based on its ability to bind to the active site on MKK7 and/or interfere with or block the ability of MKK7 to bind to its receptor. For example, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human MKK7 (SEQ ID NO: 166) selected from the group consisting of Met-142, Val-150, Lys-152, Lys-165, Met-212, Met-215, Thr-217, Lys-221, Leu-266, Cys-276 and Asp-277, or the equivalent amino acid residue(s) in a MKK7 protein of another species. Alternatively, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human MKK7 (SEQ ID NO: 166) selected from the group consisting of Met-142, Val-150, Lys-165, Met-212, Met-215, Leu-266 and Asp-277, or the equivalent amino acid residue(s) in a MKK7 protein of another species.

In certain embodiments, an anti-inflammatory polypeptide can bind to human MKK7 (SEQ ID NO: 166) with an affinity of at least −600 kcal/mol, and in certain embodiments at least −650, −700, −750, −800, −850, −900, −925, −950, −1,000 kcal/mol, or greater. The requisite binding affinity can correspond to a binding affinity that can be detected in vitro or in vivo. Alternatively, the requisite binding affinity can correspond to a binding affinity that can be detected in silico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatory polypeptides and ribonucleotide reductase (RNR), any RNR protein sequence can be used. The RNR sequence used for modeling generally folds into a functional RNR protein or a functional fragment thereof. The RNR protein sequence used for modeling can be selected based on the type of subject that the anti-inflammatory polypeptide is intended to treat (e.g., a human RNR is selected if the intended subject is a human, a bovine RNR is selected if the intended subject is a cow, etc.). The sequence used for modeling can be the yeast RNR sequence (GenBank: AJV34160.1).


(SEQ ID NO: 168)
MYVYKRDGRKEPVQFDKITARISRLCYGLDPKHIDAVKVTQRIISGVYEGVTTIELDNLAAETCA
YMTTVHPDYATLAARIAISNLHKQTTKQFSKVVEDLYRYVNAATGKPAPMISDDVYNIVMENKDK
LNSAIVYDRDFQYSYFGFKTLERSYLLRINGQVAERPQHLIMRVALGIHGRDIEAALETYNLMSL
KYYTHASPTLFNAGTPKPQMSSCFLVAMKEDSIEGIYDTLKECALISKTAGGIGLHIHNIRSTGS
YIAGTNGTSNGLIPMIRVFNNTARYVDQGGNKRPGAFALYLEPWHADIFDFIDIRKNHGKEEIRA
RDLFPALWTPDLFMKRVEENGTWTLFSPTSAPGLSDCYGDEFEALYTRYEKEGRGKTIKAQKLWY
TSEDGKTSTYNFKKLHEIAKVVTRNLNRVIDRNYYPVEEARKSNMRHRPIALGVQGLADTFMLLR
LPFDSEEARLLNIQIFETIYHASMEASCELAQKDGPYETFQGSPASQGILQFDMWDQKPYGMWDW
DLGIWDEGMKQYLITQNGSIQGLPNVPQELKDLYKTVWEISQKTIINMAADRSVYIDQSHSLNLF
LRAPTMGKLTSMHFYGWKKGLKTGMYYLRTQAASAAIQFTIDQKIADQATENVADISNLKRPSYM
PSSASYAASDFVPAAVTANATIPSLDSSSEASREASPAPTGSHSLTKGMAELNVQESKVEVPEVP
APTKNEEKAAPIVDDEETEFDIYNSKVIACAIDNPEACEMCSG.

An anti-inflammatory polypeptide can be identified, for example, based on its ability to bind to the active site on RNR and/or interfere with or block the ability of RNR to bind to its receptor. For example, the anti-inflammatory polypeptide can bind to at least one amino acid residue of human RNR (SEQ ID NO: 168) selected from the group consisting of Asn-426, Leu-427, Cys-428, Glu-430, Met-606, Pro-608 and Ala-610, or the equivalent amino acid residue(s) in a RNR protein of another species.

In certain embodiments, an anti-inflammatory polypeptide can bind to human RNR (SEQ ID NO: 168) with an affinity of at least −600 kcal/mol, and in certain embodiments at least −650, −700, −750, −800, −850, −900, −925, −950, −1,000 kcal/mol, or greater. The requisite binding affinity can correspond to a binding affinity that can be detected in vitro or in vivo. Alternatively, the requisite binding affinity can correspond to a binding affinity that can be detected in silico, e.g., using the ClusPro™ algorithm.

Excluded Polypeptides

Compositions of the invention optionally exclude polypeptides that satisfy the Structural Algorithm described herein which may have been known in the art prior to the filing of the present application. Various publications have discussed synthetic and naturally occurring anti-inflammatory polypeptides and/or polypeptides having a striapathic sequence including, for example, US Patent Application Nos. 201210270770 and 2003/0109452, and U.S. Pat. No. 6,559,281. Accordingly, one or more polypeptides and/or uses of such polypeptides described in such publications can be excluded from the scope of the presently disclosed composition and/or methods. For example, peptide RP-398 (SEQ ID NO: 155) is optionally excluded from compositions disclosed herein and/or methods of using such compositions. Moreover, any of the polypeptides disclosed in Tables 3-9, below, can be optionally excluded from compositions disclosed herein and/or methods of using such compounds.

Linked Anti-Inflammatory Polypeptide Combinations

The invention further includes any two anti-inflammatory polypeptides which have been linked together. The linkage can be formed by a peptide linker, such as a Gly-Gly-Gly (GGG), Gly-Gly-Gly-Arg (GGGR; SEQ ID NO: 412), Gly-Pro-Gly (GPG), or Gly-Pro-Gly-Arg (GPGR; SEQ ID NO: 413) sequence, that links the C-terminal end of a first anti-inflammatory polypeptide to the N-terminal end of a second anti-inflammatory polypeptide. Alternatively, the linkage can be a peptoid linker (e.g., a poly N-substituted version of any of the foregoing peptide linkers), a polymer containing g-amino acids (e.g., corresponding to any of the foregoing peptide linkers), or a non-peptide, chemical linker. The linked anti-inflammatory polypeptides can be any of the polypeptides disclosed herein (e.g., in Tables 3-9), and can include the same polypeptide being linked to form a homodimer or different polypeptides being linked to form a heterodimer. Techniques for linking peptides via peptide and non-peptide linkers are well known in the art, and the inventive polypeptide combinations are intended to encompass all such linkages.

Anti-inflammatory polypeptides can be linked to another molecule via a biodegradable linkage, such as a disulfide bond. The disulfide bond can be mediated by the sulfhydryl group of a cysteine residue found in the anti-inflammatory polypeptide and a sulfhydryl group in the other molecule. The cysteine residue can be, e.g., located at either the C-terminal or N-terminal end of anti-inflammatory polypeptide. Specific examples include RP-433 (FAKKFAKKFKC, SEQ ID NO: 384) and RP-434 (KFRKAFKRFFC; SEQ ID NO: 385), though any of the peptides disclosed herein could be similarly modified. Using a disulfide linkage of this sort, polypeptides of the invention can be conveniently linked to various types of useful molecules. For example, the linkage can be with another anti-inflammatory polypeptide (which optionally includes a C-terminal or N-terminal cysteine residue), a fluorescent label (e.g., Dylight 350), a chemotherapeutic agent (e.g., a taxol derivative formed by adding a sulfhydral group to an appropriate site on the taxol ring structure, followed by oxidation with a cysteine-containing peptide of the invention), or the like.

Linked anti-inflammatory polypeptides (e.g., homo- or heterodimers) can bind to a target molecule (e.g., a target protein, such as a pro-inflammatory signaling protein) with a binding energy that is greater than that of either monomer polypeptide alone. Thus, for example, the energy of binding of linked anti-inflammatory polypeptides to an NF-kB Class II protein (e.g., RelB) can be at least −700 kcal/mol, and in certain embodiments at least −750, −800, −900, −1000, −1100, −1200, −1250, −1300, −1350, −1400, −1425, −1450, −1475, −1500, −1525, −1550, −1575, −1600 kcal/mol, or greater. The energy of binding can be determined, e.g., in silico, in vitro, or in vivo, using methods well-known in the art (e.g., using the ClusPro™ algorithm).

Modified Polypeptides

Embodiments of the invention include the modification of any of the anti-inflammatory polypeptides of the invention, by chemical or genetic means. Examples of such modification include construction of peptides of partial or complete sequence with non-natural amino acids and/or natural amino acids in L or D forms. For example, any of the peptides disclosed herein and any variants thereof could be produced in an all-D form. Furthermore, polypeptides of the invention can be modified to contain carbohydrate or lipid moieties, such as sugars or fatty acids, covalently linked to the side chains or the N- or C-termini of the amino acids. In addition, the polypeptides of the invention can be modified to enhance solubility and/or half-life upon being administered. For example, polyethylene glycol (PEG) and related polymers have been used to enhance solubility and the half-life of protein therapeutics in the blood. Accordingly, the polypeptides of the invention can be modified by PEG polymers and the like. Polypeptides of the invention can also be modified to contain sulfur, phosphorous, halogens, metals, etc. And amino acid mimics can be used to produce polypeptides of the invention (e.g., having a structure based on the Structural Algorithm or a structure similar to any of the anti-inflammatory polypeptides disclosed herein). In certain embodiments, polypeptides of the invention that include amino acid mimics have enhanced properties, such as resistance to degradation. For example, polypeptides of the invention can include one or more (e.g., all) peptoid monomers.

Compositions

Compositions of the invention include an anti-inflammatory polypeptide that satisfies the structural algorithm described herein. For example, the anti-inflammatory polypeptide can have a striapathic region having a sequence that conforms with any one of Formulas I-LIV. In particular, the anti-inflammatory polypeptide can be any of the polypeptides listed in Table 3-9, or a fragment or variant thereof. Typically, the anti-inflammatory polypeptide included in the compositions of the invention will be a synthetic polypeptide (e.g., made by chemical synthesis and/or produced recombinantly).

The compositions of the invention can include a single anti-inflammatory polypeptide, or combinations thereof. The compositions can be substantially free of proteins and other polypeptides that do not satisfy the structural algorithm disclosed herein. As used herein, the term “substantially free of proteins and other polypeptides” means that less than 5% of the protein content of the composition is made up of proteins and other polypeptides that are not an anti-inflammatory polypeptide of the invention. A composition that is substantially free of non-anti-inflammatory polypeptides of the invention can have less than 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.01%, or less of proteins or other polypeptides that do not satisfy the structural algorithm disclosed herein. Thus, the compositions can be substantially free of blood proteins, such as serum albumin, globulins, fibrinogen, and clotting factors. Alternatively, the compositions can be substantially free of globulins, fibrinogen, and clotting factors, but can include purified or recombinantly produced serum albumin.

The compositions of the invention in certain embodiments contain an anti-inflammatory polypeptide that is not naturally found in a human or other mammal or animal. However, compositions of the invention can include an anti-inflammatory polypeptide that is naturally found in a human or other mammal or animal, provided that the composition is substantially free of biological molecules (such as non-anti-inflammatory polypeptides, nucleic acids, lipids, carbohydrates, and metabolites) that are associated with the anti-inflammatory polypeptide in vivo or co-purify with the anti-inflammatory polypeptide. As used herein, the term “substantially free of biological molecules” means that less than 5% of the dry weight of the composition is made up of biological molecules that are not anti-inflammatory polypeptides. A composition that is substantially free of such biological molecules can have less than 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.01%, or less of biological molecules that are not anti-inflammatory polypeptides. Thus, for example, the composition can be substantially free of biological molecules that are abundant in the blood, such the proteins discussed above, fatty acids, cholesterol, non-protein clotting factors, metabolites, and the like. In addition, the composition can be substantially free of cells, including red blood cells, white blood cells, and platelets, and cell fragments.

The compositions of the invention can include at least 1 mg (e.g., at least 5, 10, 20, 30, 40, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, 1000 mg, or more) of anti-inflammatory polypeptide. Thus, for example, the compositions can include an amount of anti-inflammatory polypeptide equal to about 1 mg to about 1000 mg (e.g., about 5 mg to about 900 mg, about 5 mg to about 800 mg, about 5 mg to about 700 mg, about 5 mg to about 600 mg, about 10 mg to about 500 mg, about 10 mg to about 400 mg, about 10 mg to about 300 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 150 mg, about 10 mg to about 100 mg, about 50 mg to about 500 mg, about 50 mg to about 400 mg, about 50 mg to about 300 mg, about 50 mg to about 250 mg, about 50 mg to about 200 mg, about 50 mg to about 150 mg, about 50 mg to about 100 mg, about 75 mg to about 500 mg, about 75 mg to about 400 mg, about 75 mg to about 300 mg, about 75 mg to about 250 mg, about 75 mg to about 200 mg, about 75 mg to about 150 mg, about 75 mg to about 100 mg, about 100 mg to about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 300 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, or any other range containing two of the foregoing endpoints).

The compositions of the invention can include a solution that contains at least 1 mg/ml (e.g., at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 mg/ml or more) of an anti-inflammatory polypeptide. Thus, for example, the compositions can include a solution having an anti-inflammatory polypeptide concentration of about 1 mg/ml to about 1000 mg/ml (e.g., about 5 mg/ml to about 900 mg/ml, about 5 mg/ml to about 800 mg/ml, about 5 mg/ml to about 700 mg/ml, about 5 mg/ml to about 600 mg/ml, about 5 mg/ml to about 500 mg/ml, about 10 mg/ml to about 500 mg/ml, about 10 mg/ml to about 400 mg/ml, about 10 mg/ml to about 300 mg/ml, about 10 mg/ml to about 250 mg/ml, about 10 mg/ml to about 200 mg/ml, about 10 mg/ml to about 150 mg/ml, about 10 mg/ml to about 100 mg/ml, about 50 mg/ml to about 500 mg/ml, about 50 mg/ml to about 400 mg/ml, about 50 mg/ml to about 300 mg/ml, about 50 mg/ml to about 250 mg/ml, about 50 mg/ml to about 200 mg/ml, about 50 mg/ml to about 150 mg/ml, about 50 mg/ml to about 100 mg/ml, about 75 mg/ml to about 500 mg/ml, about 75 mg/ml to about 400 mg/ml, about 75 mg/ml to about 300 mg/ml, about 75 mg/ml to about 250 mg/ml, about 75 mg/ml to about 200 mg/ml, about 75 mg/ml to about 150 mg/ml, about 75 mg/ml to about 100 mg/ml, about 100 mg/ml to about 500 mg/ml, about 100 mg/ml to about 400 mg/ml, about 100 mg/ml to about 300 mg/ml, about 100 mg/ml to about 250 mg/ml, about 100 mg/ml to about 200 mg/ml, about 10 mg/ml to about 150 mg/ml, or any other range containing two of the foregoing endpoints).

The compositions of the invention include pharmaceutical compositions. Such pharmaceutical compositions can comprise one or more anti-inflammatory polypeptides and a pharmaceutically acceptable carrier. Pharmaceutical compositions can further include a protein other than an anti-inflammatory polypeptide of the invention and/or a chemotherapeutic agent. The other protein can be a therapeutic agent, such as a therapeutic antibody. The therapeutic protein or antibody can have anti-inflammatory properties or other properties that the anti-inflammatory polypeptides of the invention augment or are augmented by. Alternatively, the other protein can be a carrier protein, such as serum albumin (e.g., HSA). The serum albumin (e.g., HAS, BSA, etc.) can be purified or recombinantly produced. By mixing the anti-inflammatory polypeptide(s) in the pharmaceutical composition with serum album, the anti-inflammatory polypeptides can be effectively “loaded” onto the serum albumin, allowing a greater amount of anti-inflammatory polypeptide to be successfully delivered to a site of inflammation. The chemotherapeutic agent can be, for example, an anti-cancer chemotherapeutic agent. Such chemotherapeutic agents include, but are not limited to, Gemcitabine, Docetaxel. Bleomycin, Erlotinib, Gefitinib, Lapatinib, Imatinib, Dasatinib, Nilotinib, Bosutinib, Crizotinib, Ceritinib, Trametinib, Bevacizumab, Sunitinib, Sorafenib, Trastuzumab, Ado-trastuzumab emtansine, Rituximab, Ipilimumab, Rapamycin, Temsirolimus, Everolimus, Methotrexate, Doxorubicin, Abraxane, Folfirinox, Cisplatin, Carboplatin, 5-fluorouracil, Teysumo, Paclitaxel, Prednisone, Levothyroxine, and Pemetrexed.

Methods

The anti-inflammatory polypeptides of the invention provide powerful tools for reducing inflammation and/or treating conditions associated with excessive inflammation (whether acute or chronic). As used herein, the terms “treat.”“treating.” and similar words shall mean stabilizing, reducing the symptoms of, preventing the occurrence of, or curing a medical condition.

Accordingly, the invention provides methods of reducing the expression level and/or activity of at least one (e.g., 2, 3, 4, 5, or more) pro-inflammatory cytokine(s) at a site of inflammation in a subject. The methods include administering an anti-inflammatory polypeptide of the invention (or, for example, a pharmaceutical composition comprising an anti-inflammatory polypeptide) to the subject. The pro-inflammatory cytokine can be selected from the group consisting of NF-kB, TNFα, IL-1, IL-6, IL-8, IL-12, IL-17, IL-23, MCP-1, MMP-1, and MMP-9. The reduction can be a reduction of at least 10% (e.g., 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more) in the expression or activity of the cytokine.

The invention also provides methods of inhibiting an increase in the expression level and/or activity of at least one (e.g., 2, 3, 4, 5, or more) pro-inflammatory cytokine(s) at a potential site of inflammation in a subject. The methods include administering an anti-inflammatory polypeptide of the invention (or, for example, a pharmaceutical composition comprising an anti-inflammatory polypeptide) to the subject. The pro-inflammatory cytokine can be selected from the group consisting of NF-kB, TNFα, IL-1, IL-6, IL-8, IL-12, IL-17, IL-23, MCP-1, MMP-1, and MMP-9. The methods can inhibit increased cytokine expression and/or activity by limiting such increases to no more than 20% (e.g., 15%, 12.5%, 10%, 7.5%, 5%, 4%, 3%, 2%, 1%, or less).

The invention also provides a method of treating or preventing a condition associated with chronic inflammation. The condition associated with chronic inflammation can be irritable bowel disease, ulcerative colitis, colitis. Crohn's disease, idiopathic pulmonary fibrosis, asthma, keratitis, arthritis, osteoarthritis, rheumatoid arthritis, auto-immune diseases, a feline or human immunodeficiency virus (FIV or HIV) infection, cancer, age-related inflammation and/or stem cell dysfunction (e.g., age-related increases in Nlrp3 expression, age-related elevation of SOCS3 in muscle stem cells, etc.), graft-versus-host disease (GVHD), keloids, scleroderma, obesity, diabetes, diabetic wounds, other chronic wounds, atherosclerosis, multiple sclerosis, Parkinson's disease. Alzheimer's disease, macular degeneration, gout, gastric ulcers, gastritis, mucositis, toxoplasmosis, and chronic viral or microbial infections (e.g., such as chronic bacterial or protozoan infections). The methods includes administering an anti-inflammatory polypeptide of the invention (or, for example, a pharmaceutical composition comprising an anti-inflammatory polypeptide) to a subject suffering from or likely to develop the condition.

The invention also provides methods of treating or preventing fibrosis. The fibrosis can be, for example, pulmonary fibrosis, dermal fibrosis, hepatic fibrosis, renal fibrosis, or fibrosis caused by ionizing radiation. The methods include administering an anti-inflammatory polypeptide of the invention (or, for example, a pharmaceutical composition comprising an anti-inflammatory polypeptide) to a subject suffering from or likely to develop fibrosis.

The invention also provides methods of treating cancer. The cancer can be colon cancer, breast cancer, leukemia, lymphoma, ovarian cancer, prostate cancer, liver cancer, lung cancer, testicular cancer, cervical cancer, bladder cancer, endometrial cancer, kidney cancer, melanoma, cancers of the thyroid or brain, or ophthalmic cancer. The methods include administering an anti-inflammatory polypeptide of the invention (or, for example, a pharmaceutical composition comprising an anti-inflammatory polypeptide) to a subject suffering from cancer.

For any of the foregoing methods, the subject can be an animal, such as a domesticated animal (e.g., a horse, cow, pig, goat, sheep, rabbit, chicken, turkey, duck, etc.), a pet (e.g., a dog, cat, rabbit, hamster, gerbil, bird, fish, etc.), a lab animal (e.g., a mouse, rat, monkey, chimpanzee, owl, fish, etc.), a zoo animal (e.g., a gorilla, orangutan, chimpanzee, monkey, elephant, camel, zebra, boar, lion, tiger, giraffe, bear, bird, etc.), a wild animal (e.g., a deer, wolf, mountain lion, bird, etc.), or a human.

In conjunction with any of the foregoing methods, the anti-inflammatory polypeptide(s) can be administered at a dose and frequency that depends on the type of animal, the size of the animal, and the condition being treated. Typically, the anti-inflammatory polypeptide is administered daily (or every other day, or weekly), in an amount between about 1 mg and about 1000 mg (e.g., about 5 mg to about 900 mg, about 5 mg to about 800 mg, about 5 mg to about 700 mg, about 5 mg to about 600 mg, about 10 mg to about 500 mg, about 10 mg to about 400 mg, about 10 mg to about 300 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 150 mg, about 10 mg to about 100 mg, about 50 mg to about 500 mg, about 50 mg to about 400 mg, about 50 mg to about 300 mg, about 50 mg to about 250 mg, about 50 mg to about 200 mg, about 50 mg to about 150 mg, about 50 mg to about 100 mg, about 75 mg to about 500 mg, about 75 mg to about 400 mg, about 75 mg to about 300 mg, about 75 mg to about 250 mg, about 75 mg to about 200 mg, about 75 mg to about 150 mg, about 75 mg to about 100 mg, about 100 mg to about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 300 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, or any other range containing two of the foregoing endpoints). The daily dose can be administered once during the day, or broken up into smaller doses that are taken at multiple time points during the day. For a human (and other similarly-sized mammals), a dose of 5 mg/kg every other day can be administered. The anti-inflammatory polypeptide can be administered for a fixed period of time (e.g., for 2-3 weeks), at intervals (e.g., administer polypeptide for 2-3 weeks, wait 2-3 weeks, then repeat the cycle), or until such time as the pro-inflammatory cytokine levels have been reduced or stabilized, the chronic inflammatory condition or fibrosis has ameliorated, or the cancer has gone into remission.

The administration of the anti-inflammatory polypeptides (or pharmaceutical compositions comprising such polypeptides) in conjunction with any of the foregoing methods can be performed intravenously, intraperitoneally, parenteral, orthotopically, subcutaneously, topically, nasally, orally, sublingually, intraocularly, by means of an implantable depot, using nanoparticle-based delivery systems, microneedle patch, microspheres, beads, osmotic or mechanical pumps, and/or other mechanical means.

In conjunction with any of the foregoing methods, the anti-inflammatory polypeptides (or pharmaceutical compositions comprising such polypeptides) can be administered in combination with another drug designed to reduce or prevent inflammation, treat or prevent chronic inflammation or fibrosis, or treat cancer. In each case, the anti-inflammatory polypeptide can be administered prior to, at the same time as, or after the administration of the other drug. For the treatment of cancer, the anti-inflammatory polypeptide(s) can be administered in combination with a chemotherapeutic agent selected from the group consisting of steroids, anthracyclines, thyroid hormone replacement drugs, thymidylate-targeted drugs, Chimeric Antigen Receptor/T cell therapies, and other cell therapies. Specific chemotherapeutic agents include, for example, Gemcitabine, Docetaxel, Bleomycin, Erlotinib, Gefitinib, Lapatinib, Imatinib, Dasatinib, Nilotinib, Bosutinib, Crizotinib. Ceritinib, Trametinib, Bevacizumab, Sunitinib, Sorafenib, Trastuzumab, Ado-trastuzumab emtansine, Rituximab, Ipilimumab, Rapamycin, Temsirolimus, Everolimus, Methotrexate, Doxorubicin, Abraxane, Folfirinox, Cisplatin, Carboplatin, 5-fluorouracil, Teysumo, Paclitaxel, Prednisone, Levothyroxine, and Pemetrexed.

Alternatively, for the methods of treating cancer, the anti-inflammatory polypeptide(s) (or pharmaceutical compositions comprising such polypeptides) can be administered in combination with radiation therapy. Again, the anti-inflammatory polypeptide(s) can be administered prior to, or after the administration of the radiation therapy.

Any of the foregoing methods of the invention further include a step of assessing the efficacy of the therapeutic treatment. Because the anti-inflammatory polypeptides of the invention have a demonstrable ability to reduce tissue inflammation and suppress the excessive production of inflammatory mediators such as IL-1, IL-6, IL-12, and TNFα, both in tissues and in serum (data not shown), the efficacy of the therapeutic treatment can be assessed by measuring the levels of such cytokines (e.g., in the serum) to determine whether the levels have responded appropriately to the treatment. Depending on the cytokine levels, the dosage of anti-inflammatory polypeptide(s) can be adjusted up or down, as needed.

EXAMPLES

Example 1: Peptide Designs

Polypeptides were designed in silico to include a striapathic region of alternating Xm and Yn modules, with each Xm module having one to five hydrophilic amino acid residues and each Yn module having one to five hydrophobic residues.

Initial designs focused on polypeptides consisting of a striapathic region having a total length of around 10 amino acid residues, with each Xm module having one or two hydrophilic amino acid residues and each Yn module having one or two hydrophobic residues, and with the ratio of hydrophobic to hydrophilic amino acid residues being around 1:1. Such polypeptides were predicted to have an amphipathic, helical secondary structure, with a hydrophobic surface on one side of the helix and a hydrophilic surface on the opposite side of the helix.

Additional peptide designs were subsequently generated that maintained a total length of around 10 amino acid residues, but expanded the number of possible amino acid residues in a hydrophilic or hydrophobic module from two to three and varied the hydrophobic to hydrophilic ratio. For example, larger hydrophobic modules having three hydrophobic amino acid residues were coupled with shorter hydrophilic modules having one hydrophilic amino acid residue, giving rise to polypeptides predicted to have a stronger hydrophobic character. Such peptides were predicted to maintain an amphipathic, helical secondary structure, but have a larger hydrophobic surface on one side of the helix and a correspondingly smaller hydrophilic surface on the other side. Similarly, larger hydrophilic modules having three hydrophilic amino acid residues were coupled with shorter hydrophobic modules having one hydrophobic amino acid residue, giving rise to peptides having a stronger hydrophilic character. Such peptides were also predicted to maintain an amphipathic, helical secondary structure, but have a larger hydrophilic surface on one side of the helix and a correspondingly smaller hydrophobic surface on the other side.

Other peptide designs included: polypeptides having modules of four or five hydrophilic amino acid residues and/or four or five hydrophobic; polypeptides having a total length of around 10 amino acid residues but lacking hydrophobic amino acid residues; polypeptides having hydrophilic and hydrophobic modules each consisting of a single amino acid residue; and proline-rich polypeptides. Finally, larger polypeptides comprising two of the smaller peptide designs were also generated.

Exemplary polypeptides designed as described above are presented in Tables 3-9, below. To provide greater clarity into the types of polypeptides that have been developed, the peptides have been organized into Classes. Typically, the striapathic region of a specific Class of polypeptides shares a common sequence of hydrophobic and hydrophilic modules that is at least six or seven amino acid residues long. However, because the data indicates that polypeptides that have the same sequence but reversed N-terminal to C-terminal orientation have surprisingly similar anti-inflammatory activities, efforts have been made to keep such polypeptides in the same Class. Accordingly, some polypeptides have been grouped into the same Class even though the common sequence of hydrophobic and hydrophilic modules is less than six amino acid residues long. In addition, some of the polypeptides could have been grouped differently because they contain the common sequence of hydrophobic and hydrophilic modules of more than one Class. Thus, while providing a helpful framework for organizing the polypeptides around structural and functional similarities, the classification system does not capture all aspects of the relationships between different polypeptides.

Table 3 presents various Class I polypeptides, which have a striapathic region that includes a sequence corresponding to Formula I (i.e., Y1a-Y1b-Y1c-X1a-Y2a-Y2b-Y2c). Two different types of Class I polypeptides are presented in Table 3: peptides that have a striapathic region consisting of a sequence corresponding to Formula II (i.e., Y1a-Y1b-Y1c-X1a-Y2a-Y2b-Y2c-X2a-Y3a-X3a); and peptide that have a striapathic region consisting of a sequence corresponding to Formula III (i.e., X2a-Y3a-X3a-Y1a-Y1b-Y1c-X1a-Y2a-Y2b-Y2c). In addition, a peptide having a striapathic region having a sequence corresponding to Formula I, but not Formulas II or III, is presented.


TABLE 3
Class I Polypeptides
RelB
Binding E
RP #
Sequence
(kCal/mol)
Formula
SEQ ID NO:
394
NFNFFFRFFF
−1,286.6
III
33
108
WWWRWWWEWQ
−1,278.0
II
34
109
EFNFFFRFFF
−1,247.7
III
35
110
DFEFFFRFFF
−1,232.0
III
36
111
QFEFFFRFFF
−1,226.8
III
37
112
EFEFFFRFFF
−1,216.0
III
38
113
FFFRFFFEFQ
−1,208.9
II
39
114
FFFRFFFEFE
−1,176.3
II
40
115
FFFRFFFEFD
−1,172.3
II
41
116
FFFRFFFNFE
−1,162.6
II
42
117
FFFRFFFDFE
−1,147.7
II
43
118
FFFRFFFNFN
−1,139.9
II
44
119
FFFHFFFEFQ
−1,135.4
II
45
120
FFFHFFFNFE
−1,126.4
II
46
121
FFFHFFFEFN
−1,126.4
II
47
122
EFNFFFHFFF
−1,125.1
III
48
123
FFFRFFFEFN
−1,124.5
II
49
125
FFFHFFFEFE
−1,115.4
II
50
126
QFEFFFHFFF
−1,114.4
III
51
127
FFFHFFFEFD
−1,114.3
II
52
128
FFFHFFFDFE
−1,111.4
II
53
129
YYYRYYYEYQ
−1,110.2
II
54
130
NFEFFFHFFF
−1,109.1
III
55
131
FFFKFFFKFE
−1,107.0
II
56
133
EFDFFFRFFF
−1,103.4
III
57
135
FFFHFFFDFD
−1,102.4
II
58
136
FFFHFFFNFN
−1,100.4
II
59
137
FFFRFFFDFD
−1,100.3
II
60
138
FFFKFFFKFN
−1,098.2
II
61
139
FFFKFFFEFE
−1,095.1
II
62
140
FFFEFFFKFE
−1,091.8
II
63
141
FFFQFFFQFQ
−1,088.8
II
64
143
FFFKFFFQFQ
−1,084.4
II
65
144
FFFKFFFNFN
−1,083.5
II
66
145
FFFNFFFNFN
−1,083.3
II
67
146
FFFKFFFEFQ
−1,082.6
II
68
148
FFFKFFFKFQ
−1,080.0
II
69
149
FFFKFFFQFK
−1,079.6
II
70
150
FFFKFFFKFD
−1,077.4
II
71
152
FFFKFFFDFD
−1,074.5
II
72
153
FFFNFFFKFN
−1,074.2
II
73
154
FFFDFFFDFD
−1,073.5
II
74
155
FFFKFFFEFK
−1,073.3
II
75
156
FFFKFFFDFK
−1,072.6
II
76
157
FFFEFFFEFE
−1,070.8
II
77
158
FFFDFFFKFD
−1,070.7
II
78
159
FFFKFFFKFK
−1,070.7
II
79
160
FFFEFFFKFK
−1,069.7
II
80
161
FFFQFFFKFK
−1,069.6
II
81
162
FFFKFFFNFK
−1,069.2
II
82
163
FFFNFFFKFK
−1,066.7
II
83
164
FFFQFFFKFQ
−1,062.5
II
84
165
FFFDFFFKFK
−1,061.9
II
85
179
LLLRLLLELQ
−966.7
II
86
395
FVFKFVFKFV
−917.2
I
87
211
CCCRCCCECQ
−818.2
II
88
230
MMMRMMMEMQ
−774.6
II
89
232
VVVRVVVEVQ
−771.6
II
90
258
IIIRIIIEIQ
−699.2
II
91
267
GGGRGGGEGQ
−640.4
II
92
268
PPPRPPPEPQ
−627.1
II
93
271
TTTRTTTETQ
−614.4
II
94
273
AAARAAAEAQ
−609.4
II
95
280
AAAKAAAKAA
−556.0
II
96
281
AAAEAAAEAE
−541.6
II
97
287
SSSRSSSESQ
−499.3
II
98

Table 4 presents some quasi-Class I polypeptides. These peptides include a sequence similar to the striapathic sequence of Formula II (i.e., Y1a-Y1b-Yc-X1a-Y2a-Y2b-Y2c-X2a-Y3a-X3a), but the hydrophobic amino acid residues have all been replaced with a particular hydrophilic amino acid residue.


TABLE 4
Quasi-Class I Polypeptides
RelB
Binding E
RP #
Sequence
(kCal/mol)
Formula
SEQ ID NO:
173
HHHRHHHEHQ
−1,002.2
II*
99
195
RRRRRRRERQ
−855.2
II*
100
275
QQQRQQQEQQ
−575.6
II*
101
276
EEEREEEEEQ
−569.5
II*
102
284
NNNRNNNENQ
−522.7
II*
103
288
DDDRDDDEDQ
−463.6
II*
104
290
KKKRKKKEKQ
−423.7
II*
105
*These peptides do not comply with the sequence requirements of Formula II, but instead represent an “all hydrophilic” variation on the sequence requirements of Formula II.

Table 5 presents various Class II, Sub-class 1 polypeptides. The presented peptides have a striapathic region consisting of a sequence corresponding to Formula X (i.e., Y1a-Y1b-X1a-X1b-Y2a-Y2b-X2b-X2b-Y3a-X3a), or a striapathic region consisting of a sequence corresponding to Formula XI (i.e., X1a-Y1a-X2a-X2b-Y2a-Y2b-X3a-X3b-Y3a-Y3b).


TABLE 5
Class II, Sub-class 1 Polypeptides
RelB
Binding E
RP#
Sequence
(kCal/mol)
Formula
SEQ ID NO:
124
FFQKFFKRWR
−1,121.3
X
106
132
FFRKFFKRFR
−1,104.8
X
107
134
RFRKFFKRFF
−1,103.3
XI
108
142
RFRKFFKQFF
−1,085.5
XI
109
147
FFQKFFKRFR
−1,080.3
X
110
151
RWRKFFKQFF
−1,077.0
XI
111
166
FFEHFWKEFN
−1,044.8
X
112
167
FFQHFWKQFN
−1,024.9
X
113
168
QFNHFFKEFF
−1,022.8
XI
114
169
FFDKFFHDFQ
−1,014.2
X
115
170
QFDHFFKDFF
−1,011.9
XI
116
171
FFEKFFHNFQ
−1,009.9
X
117
172
NFEKWFHEFF
−1,007.9
XI
118
175
LFRRAFKQLD
−989.5
X
119
177
NFQKWFHQFF
−976.3
XI
120
182
KFRKAFKRFF
−944.8
XI
121
183
FFRKFAKRFK
−933.2
X
122
185
FFKKFFKKFK
−920.6
X
123
186
KFKKFFKKFF
−919.6
XI
124
424
KARKAFKRFF
−910.2
XI
125
190
WVKDAMQHLD
−888.7
X
126
194
FFKKFAKKFK
−859.1
X
127
198
FAEKFFKNFK
−850.4
X
128
199
KFNKFFKEAF
−847.1
XI
129
200
FAKQFFNKFK
−846.0
X
130
201
KFNKAFKQAF
−837.8
XI
131
202
KFNKAFKQAF
−837.8
XI
131
204
FAQKFFKDFK
−835.9
X
133
206
FAEEFAEEFE
−823.1
X
134
207
KFKKFFKKAF
−820.7
XI
135
209
KFKNFFQKAF
−819.1
XI
136
210
KFKNFFQKAF
−819.1
XI
136
212
FAKQFANKFK
−817.9
X
138
213
KFKNAFQKAF
−815.2
XI
139
214
KFKNAFQKAF
−815.2
XI
139
215
FAKKFFKKFK
−814.0
X
141
216
KFKKAFKKFF
−811.2
XI
142
218
FAEKFAEKFE
−807.6
X
143
219
DLHQMADKVW
−807.6
XI
144
425
KARKAAKRFF
−800.3
XI
145
225
FAKNFAKKFK
−794.0
X
146
227
FAEKFAKNFK
−786.6
X
147
233
KFKKAFKKAF
−771.2
XI
148
234
FAKNFAKNFK
−769.8
X
149
235
FAKEFAKEFE
−768.9
X
150
236
KFDKAFKQAF
−766.2
XI
151
237
KFDKAFKQAF
−766.2
XI
151
238
FAEKFAKKFK
−765.1
X
153
239
FAEKFAEKFK
−764.2
X
154
398
FAKKFAKKFK
−760.3
X
155
241
FAKNFAKNFN
−758.7
X
156
242
FAQKFAKNFK
−758.6
X
157
243
FANNFANNFN
−755.2
X
158
244
FANNFANNFN
−755.2
X
158
245
FANKFANKFN
−754.0
X
160
246
FANKFAKKFK
−752.2
X
161
247
FAQKFAKDFK
−750.7
X
162
250
FAKEFAKEFK
−745.7
X
163
251
FANKFANKFK
−739.7
X
164
252
KFDKFFKQAF
−739.1
XI
165
253
KFDKFFKQAF
−739.1
XI
165
254
KFNKAFKEAF
−738.4
XI
167
255
KFNKAFKEAF
−738.4
XI
167
256
FAKEFAKKFK
−702.8
X
169
426
KARKAAKRAF
−634.5
XI
170
427
KARKAAKRAA
−578.1
XI
171
285
AAEEAAEEAE
−511.6
X
172
387
AAKKAAKKAK
−301.6
X
173

Table 6 presents polypeptides that fall into a variety of different Classes, including: Class II peptides (having a striapathic region that includes a sequence corresponding to any of Formulas VI to XVI); Class II, Sub-class 2 (having a striapathic region that includes a sequence corresponding to Formulas VIII and XII); Class II, Sub-class 3 (having a striapathic region that includes a sequence corresponding to Formula IX); Class II, Sub-class 4 (having a striapathic region that includes a sequence corresponding to Formulas XIV and XV); Class II, Sub-class 5 (having a striapathic region that includes a sequence corresponding to Formulas XIII and XVI); Class III peptides (having a striapathic region that includes a sequence corresponding to any of Formulas XVII to XX); Class III, Sub-class 1 peptides (having a striapathic region that includes a sequence corresponding to Formulas XIX or XX); Class IV peptides (having a striapathic region that includes a sequence corresponding to Formulas IV and V); Class V peptides (having a striapathic region that includes a sequence corresponding to Formula XXI); Class VI peptides (having a striapathic region that includes a sequence corresponding to Formulas XXII and XXIII); Class VII peptides (having a striapathic region that includes a sequence corresponding to any of Formulas XXIV to XXVI); Class VIII peptides (having a striapathic region that includes a sequence corresponding to any of Formulas XXVII to XXXII): Class VIII, Sub-class 3 and 4 peptides (having a striapathic region that includes a sequence corresponding to Formulas XXXI and XXXII, respectively); Class IX peptides (having a striapathic region that includes a sequence corresponding to any of Formulas XXXIII to XXXVIII); Class IX, Sub-class 3 and 4 peptides (having striapathic regions that include a sequence corresponding to Formulas XXXVII and XXXVIII, respectively); and Class XIII (having a striapathic region that includes a sequence corresponding to Formula L). Because polypeptides of Class VIII, Sub-class 3 and Class IX, Sub-class 3 share the same sequence of hydrophobic and hydrophilic modules, but reversed N-terminal to C-terminal orientation, they could have been grouped into the same Class and Sub-class. Similarly, because polypeptides of Class VIII, Sub-class 4 and Class IX, Sub-class 4 share the same sequence of hydrophobic and hydrophilic modules, but reversed N-terminal to C-terminal orientation, they could have been grouped into the same Class and Sub-class.


TABLE 6
Class II to Class IX and
Class XIII Polypeptides
RelB
Binding E
RP #
Sequence
(kCal/mol)
Formula
SEQ ID NO:
396
FVKFVKFVKF
−1,039.7
L
174
405
KRKAFRKFFF
−1,026.6
XIV
175
174
LHKMYNQVW
−1,000.2
VII
176
176
WVQNYMKHL
−979.3
VII
177
178
RLVEMMRQIW
−972.2
XX
178
180
FLKRLLQEI
−955.9
VII
179
181
LRLLHRLL
−950.2
XVII
180
184
WVRDSMKHL
−925.6
VII
181
408
KFFRKKFRFA
−917.4
XXII
182
187
WVQRVVEKFL
−906.4
IX
183
416
AFFRRFKFKK
−904.1
XXV
184
188
LFKEVVRQVW
−902.9
IX
185
189
MDKIYDQVWK
−893.3
VIII
186
388
FVKKFVKKFV
−891.9
X
187
417
KKFKFRRFFA
−888.8
XXVI
188
191
WVRDVVRSMD
−874.1
XIX
189
192
ELSNIYERVW
−872.4
XX
190
193
WIQRMMEVLR
−866.9
XIX
191
404
FFFKRFAKRK
−856.7
XV
192
196
LHKMSDRVW
−852.4
VII
193
197
WVREYINSLE
−851.2
XIX
195
402
FFKKRFAFRK
−851.0
XXXI
196
203
KWVQDYIKDM
−837.0
XII
197
409
AFRFKKRFFK
−832.7
XXIII
198
205
LLRHLLRL
−830.0
XVII
199
208
WIKKLLESSQ
−819.7
XIX
200
217
DMSRVVDRVW
−810.4
XX
201
220
FEEEFEEEFE
−804.8
V
202
221
WVKNSINHL
−803.7
VII
203
222
LTKKGRRFC
−799.7
XXI
204
223
IEQLLRKLF
−796.8
VII
205
224
LHNISNKVW
−794.5
VII
206
226
CFRRGKKTL
−786.7
XXI
207
229
IVRRADRAAV
−781.5
XXI
208
231
TVERFKNLS
−771.8
XXI
209
240
QSSELLKKIW
−761.9
XX
210
248
SLNKFREVT
−750.5
XXI
211
249
LIKQIVKKLF
−750.5
IX
212
397
FAKKFAKKF
−739.3
VII
194
415
KKKFFF
−706.8
XXVII
213
257
LYKKIIKKLL
−699.8
IX
214
259
FKKKFKKKFK
−686.5
V
215
260
VAARDARRVI
−684.6
XXI
216
261
FLKKVIQKIL
−679.4
IX
217
262
LIKEIIKQVM
−668.4
IX
218
263
LLKKIIKKYL
−666.7
IX
219
264
AFFEEEAEFE
−652.2
XXXVIII
220
265
KKWVQDSMK
−650.1
XVIII
221
266
NFANKVQEVA
−644.1
XXI
222
269
AVEQVKNAFN
−621.1
XXI
223
272
MVQKIIEKIL
−613.1
IX
224
274
KMSDQVWKK
−595.9
XVIII
225
277
MVKKIIEKM
−569.2
VII
226
278
ALKKQVIKKI
−559.1
XVI
227
279
IKKIVQKKLA
−556.7
XIII
228
282
AFFKKKAKFK
−537.6
XXXVIII
229
283
MKEIIKVM
−533.1
VII
230
286
AEEEAEEEAE
−504.4
V
231
289
AKKKAKKKAK
−431.6
V
232
414
KKKAAA
0.0
XXVII
233

Table 7 presents polypeptide of Classes VIII through XI. All of the peptides presented in Table 7 have a striapathic region that includes a hydrophilic module having four or five hydrophilic amino acid residues and/or a hydrophobic module having four or five hydrophobic amino acid residues. Class VIII, Sub-class 1 peptides have a striapathic region that includes a sequence corresponding to Formulas XXVIII or XXIX; Class VIII, Sub-class 2 peptides have a striapathic region that includes a sequence corresponding to Formula XXX; Class IX, Sub-class 1 peptides have a striapathic region that includes a sequence corresponding to Formulas XXXIV or XXXV; Class IX, Sub-class 2 peptides have a striapathic region that includes a sequence corresponding to Formula XXXVI; Class X peptides have a striapathic region that includes a sequence corresponding to any of Formulas XXXIX to XLIII; and Class XI peptides have a striapathic region that includes a sequence corresponding to any of Formulas XLIV to XLVIII. Because polypeptides of Class VIII, Sub-class 1 and Class IX, Sub-class 1 share the same sequence of hydrophobic and hydrophilic modules, but reversed N-terminal to C-terminal orientation, they could have been grouped into the same Class and Sub-class. Similarly, because polypeptides of Class VIII, Sub-class 2 and Class IX, Sub-class 2 share the same sequence of hydrophobic and hydrophilic modules, but reversed N-terminal to C-terminal orientation, they could have been grouped into the same Class and Sub-class.


TABLE 7
Class VIII to XI Polypeptides
RelB
Binding E
RP #
Sequence
(kCal/mol)
Formula
SEQ ID NO:
406
KRKKRFAFFF
−993.5
XXX
234
422
RKRKFFAFFK
−948.2
XLVIII
235
407
FFFAFRKKRK
−914.7
XXXVI
236
400
FRKKRFAFFK
−900.5
XXIX
237
419
FFFRRKKKFA
−881.9
XLII
238
401
KFFAFRKKRF
−880.1
XXXV
239
423
KFFAFFKRKR
−877.1
XLV
240
411
KKKKKFFFFF
−863.7
XXX
241
418
AFKKKRRFFF
−854.1
XLI
242
428
KRKKRAAFFF
−842.0
XXX
243
420
KKFFAFFRKR
−840.2
XLVI
244
421
RKRFFAFFKK
−835.5
XLVII
245
429
KRKKRAAAFF
−758.1
XXX
246
413
KKKKFFFF
−715.8
XXVIII
247
430
KRKKRAAAAF
−676.7
XXX
248
270
KKKAFFFAKK
−614.4
XLVII
249
431
KRKKRAAAAA
−544.9
XXX
250
410
KKKKKAAAAA
−385.3
XXX
251
412
KKKKAAAA
−382.8
XXVIII
252

Table 8 presents polypeptides of Class XII and Class XIV. Class XII peptides have a striapathic region that includes a sequence corresponding to Formula XLIX (i.e., Y1a-X1a-Y2a-X2a-Y3a-X3a). Class XII peptides are predicted to adopt a beta-strand secondary structure. Class XIV peptides are proline-rich peptides that have a striapathic region that includes a sequence corresponding to one of Formulas LI-LIV.


TABLE 8
Beta-Strand and Proline-Rich Polypeptides
RelB
Binding E
RP #
Sequence
(kCal/mol)
Formula
SEQ ID NO:
393
FKFKFKFKF
−1,193.2
XLIX
253
391
FRFKFKFR
−1,190.8
XLIX
254
392
RFQFKFRF
−1,170.3
XLIX
255
390
FRFKFKF
−1,083.3
XLIX
256
389
FRFKFA
−1,009.8
XLIX
257
449
RRFPRPPFF
−1,116.8
LI
258
450
FFPPRPFRR
−1,100.0
LII
259
448
LYPPRPFRR
−1,059.3
LII
260
447
RRIPRPPYL
−1,050.5
LI
261
452
PFRPPPRPRF
−1,012.2
LIII
262
451
PRPRPPPRFF
−1,002.1
LIV
263
444
FFPPKPFKK
−954.8
LII
264
441
KKIPKPPYL
−922.1
LI
265
446
PFKPPPKPKP
−882.3
LIII
266
445
PKPKPPPKFP
−866.3
LIV
267
442
LYPPKPIKK
−846.6
LII
268
443
KKFPKPPFF
−802.8
LI
269

Table 9 presents fusion peptides, which include combinations of Class I, Class II, and/or Class III peptides linked together by a peptide bond and, optionally, a short peptide linker (e.g., a tri-glycine (GGG) linker).


TABLE 9
Peptide Combinations
RelB
Binding E
RP #
Sequence
(kCal/mol)
Formula
SEQ ID NO:
292
EFEFFFRFFFGGGEFEFFFRFFF
−1,606.1
III + III
270
293
QFEFFFRFFFGGGQFEFFFRFFF
−1,602.0
III + III
271
294
DFEFFFRFFFGGGDFEFFFRFFF
−1,591.8
III + III
272
295
EFNFFFRFFFGGGEFNFFFRFFF
−1,591.8
III + III
273
296
FFFRFFFEFQFFFRFFFEFQ
−1,511.6
II + II
274
297
FFFRFFFEFQGGGFFFRFFFEFQ
−1,511.5
II + II
275
298
RWRKFFKRFFQFEFFFRFFF
−1,505.2
XI + III
276
299
RWRKFFKRFFGGGFFFRFFFNFN
−1,501.3
XI + II
277
300
RFRKFFKRFFQFEFFFRFFF
−1,486.0
XI + III
278
301
RFRKFFKRFFGGGFFFRFFFNFN
−1,485.0
XI + II
279
302
RWRKFFKRFFGGGFFFRFFFEFQ
−1,479.6
XI + II
280
303
RFRKFFKRFFGGGFFFRFFFEFQ
−1,476.8
XI + II
281
304
EFEFFFRFFFEFEFFFRFFF
−1,476.0
III + III
282
305
RWRKFFKRFFNFNFFFRFFF
−1,474.2
XI + III
283
306
QFEFFFRFFFQFEFFFRFFF
−1,467.0
III + III
284
307
RWRKFFKRFFGGGNFNFFFRFFF
−1,464.2
XI + III
285
308
EFNFFFRFFFEFNFFFRFFF
−1,460.5
III + III
286
309
RFRKFFKRFFNFNFFFRFFF
−1,458.4
XI + III
287
310
FFRKFFKRFRGGGNFNFFFRFFF
−1,447.1
X + III
288
311
RFRKFFKRFFGGGNFNFFFRFFF
−1,432.1
XI + III
289
312
DFEFFFRFFFDFEFFFRFFF
−1,430.0
III + III
290
313
RWRKFFKRFFFFFRFFFEFQ
−1,427.4
XI + II
291
314
RFRKFFKRFFFFFRFFFEFQ
−1,425.6
XI + II
292
315
FFRKFFKRFRGGGFFFRFFFNFN
−1,420.6
X + II
293
316
FFRKFFKRWRGGGFFFRFFFNFN
−1,417.5
X + II
294
317
RFRKFFKRFFFFFRFFFNFN
−1,406.6
XI + II
295
318
FFRKFFKRFRFFFRFFFEFQR
−1,402.0
X + II
296
291
FFEHFWKEFNGGGNFQKWFHQFF
−1,401.6
X + XI
297
319
FFRKFFKRWRQFEFFFRFFF
−1,400.7
X + III
298
320
RWRKFFKRFFFFFRFFFNFN
−1,397.9
XI + II
299
321
NFQKWFHQFFGGGFFEHFWKEFN
−1,396.0
XI + X
300
322
FFRKFFKRWRGGGNFNFFFRFFF
−1,394.4
X + III
301
323
FFRKFFKRWRFFFRFFFEFQR
−1,394.3
X + II
302
324
FFRKFFKRWRNFNFFFRFFF
−1,393.7
X + III
303
325
FFRKFFKRFRGGGFFFRFFFEFQR
−1,386.8
X + II
304
326
FFRKFFKRFRQFEFFFRFFF
−1,382.8
X + III
305
327
FFRKFFKRFRNFNFFFRFFF
−1,378.2
X + III
306
328
RFRKFFKRFFGGGQFEFFFRFFF
−1,368.5
XI + III
307
329
FFRKFFKRWRGGGFFFRFFFEFQR
−1,354.5
X + II
308
330
FFRKFFKRFRGGGQFEFFFRFFF
−1,352.8
X + III
309
331
FFRKFFKRWRGGGQFEFFFRFFF
−1,352.2
X + III
310
332
RWRKFFKRFFGGGQFEFFFRFFF
−1,349.8
XI + III
311
333
QFNHFFKEFGGGQFNHFFKEFF
−1,340.0
VII + XI
312
334
FFRKFFKRFRFFFRFFFNFN
−1,337.5
X + II
313
335
FFRKFFKRWRFFFRFFFNFN
−1,337.0
X + II
314
336
FFEHFWKEFNGGGFFEHFWKEFN
−1,325.5
X + X
315
337
FFEHFWKEFGGGNFQKWFHQFF
−1,324.8
VII + XI
316
338
NFQKWFHQFGGGFFEHFWKEFN
−1,317.9
VII + X
317
339
FFEHFWKEFNGGGLHKMYNQVW
−1,315.4
X + VII
318
340
NFQKWFHQFFGGGNFQKWFHQFF
−1,309.9
XI + XI
319
341
FAKKFAKKFKGGGNFQKWFHQFF
−1,308.3
X + XI
320
342
FFEKFFHNFQGGGFFEKFFHNFQ
−1,304.6
X + X
321
343
FFQHFWKQFNGGGFFQHFWKQFN
−1,300.2
X + X
322
344
NFQKWFHQFFNFQKWFHQFF
−1,293.5
XI + XI
323
345
FAKKFAQKFKGGGNFQKWFHQFF
−1,291.9
X + XI
324
346
FAKKFAKKFKGGGQFEFFFRFFF
−1,290.9
X + III
325
347
QFNHFFKEFQFNHFFKEFF
−1,279.8
VII + XI
326
348
FAKKFAKKFKGGGDFEFFFRFFF
−1,278.4
X + III
327
349
FFEHFWKEFNGGGWVQNYMKHL
−1,268.8
X + VII
328
350
FAKKFAKKFKQFEFFFRFFF
−1,268.5
X + III
329
351
FFQHFWKQFNFFQHFWKQFN
−1,263.2
X + X
330
352
FFEHFWKEFNFFEHFWKEFN
−1,251.5
X + X
331
353
NFEKWFHEFFNFEKWFHEFF
−1,247.0
XI + XI
332
354
FAKKFAKKFKGGGQFNHFFKEFF
−1,244.6
X + XI
333
355
NFEKWFHEFFGGGNFEKWFHEFF
−1,241.4
XI + XI
334
356
FAKKFAKKFKGGGFFFRFFFEFQ
−1,237.9
X + II
335
357
FAKKFAKKFKDFEFFFRFFF
−1,235.3
X + III
336
358
QFNHFFKEFFGGGQFNHFFKEFF
−1,230.0
XI + XI
337
359
FAKKFAKKFKGGGEFEFFFRFFF
−1,221.7
X + III
338
360
FAKKFAKKFKGGGEFNFFFRFFF
−1,221.0
X + III
339
361
FAKKFAKKFKGGGNFEKWFHEFF
−1,212.3
X + XI
340
362
FAKKFAKKFKGGGFFEKFFHNFQ
−1,210.8
X + X
341
363
QFNHFFKEFFQFNHFFKEFF
−1,208.6
XI + XI
342
364
FFEKFFHNFQFFEKFFHNFQ
−1,207.5
X + X
343
365
FAKKFAKKFKEFEFFFRFFF
−1,204.2
X + III
344
366
FAKKFAKKFKEFNFFFRFFF
−1,187.6
X + III
345
367
FAKKFAKKFKFFEHFWKEFN
−1,168.1
X + X
346
368
FAKKFAKKFKFFFRFFFEFQ
−1,166.4
X + II
347
369
FAKKFAKKFKLHKMYNQVW
−1,159.5
X + VII
348
370
FAKKFAKKFKGGGFFEHFWKEFN
−1,140.4
X + X
349
371
FAKKFAKKFKGGGWVQNYMKHL
−1,130.4
X + VII
350
372
FAKKFAKKFKNFQKWFHQFF
−1,126.1
X + XI
351
373
FAKKFAKKFKFFQHFWKQFN
−1,119.8
X + X
352
374
FAKKFAKKFKGGGFFQHFWKQFN
−1,119.6
X + X
353
375
FAKKFAKKFKWVQNYMKHL
−1,119.2
X + VII
354
376
FAKKFAKKFKQFNHFFKEFF
−1,108.3
X + XI
355
377
FAKKFAKKFKGGGLHKMYNQVW
−1,100.3
X + VII
356
378
FAKKFAKKFKNFEKWFHEFF
−1,081.4
X + XI
357
379
FAKKFAKKFKFFEKFFHNFQ
−1,046.8
X + X
358
380
FAKKFAKKFKGGGAFFKKKAKFK
−950.9
X +
359
XXXVIII
381
AFFKKKAKFKGGGAFFKKKAKFK
−935.5
XXXVIII +
360
XXXVIII
382
KFKKAFKKAFKFKKAFKKAF
−925.2
XI + XI
361
383
KFKKAFKKAFGGGKFKKAFKKAF
−923.8
XI + XI
362
384
FAKKFAKKFKGGGFAKKFAKKFK
−909.2
X + X
363
385
FAKKFAKKFKAFFKKKAKFK
−839.9
X +
364
XXXVIII
228
PSRKSMEKSVAKLLNKIAKSEP
−782.4
IX + XVIII
365
386
AFFKKKAKFKAFFKKKAKFK
−716.0
XXXVIII +
366
XXXVIII

In each of Tables 3-9, the RP# is a randomly assigned designation used to identify specific peptide sequences. The “Binding E” (see column 3 in each of the Tables) corresponds to a predicted measure of the energy released when individual peptides bind to the protein dimerization domain of RelB, an NFkB Class II protein (see Example 2, below).

Example 2: Predicted Binding of Peptides to Rel B

To identify peptides having anti-inflammatory activity, the NF-kB complex was selected as a target, since it is known to be a key component in the signaling pathways that regulate inflammation. Dimerization of NF-kB (either homologous or heterologous), which is mediated by the dimerization domains found in NF-kB Class II proteins (e.g., RelA, RelB, cRel, NF-kB1, and NF-kB2), is essential for activation of the NF-kB complex and its generation of pro-inflammatory signals. Accordingly, peptide designs were selected for their ability to specifically bind to the dimerization domain of RelB (NCBI Acc. No. NP_033072.2), with the goal that such binding would inhibit NF-kB dimerization and activation.

Peptide binding to the dimerization domain of Rel B was evaluated in silico, using the web-based ClusPro™ algorithm developed at Boston University. The ClusPro™ algorithm filters docked conformations between a protein target and a putative ligand and determines surface complementarity, ranking the conformations based on their clustering properties. The free energy filters select complexes with the lowest desolvation and electrostatic energies. Clustering is then used to smooth the local minima and to select the ones with the broadest energy wells, a property associated with the free energy at the binding site. Using this method, it is possible to evaluate the affinity a ligand possesses for a particular target, whereupon the ligands can be ranked and then tested for biological activity in vitro or in vivo.

The binding energies calculated by the ClusPro™ algorithm are shown for each of the peptides in Tables 3-9, in the third columns of the tables. In each of Tables 3-9, the peptides are ranked according to the calculated RelB binding energy, from highest to lowest binding energy. The RelB binding energies were used to explore the structure-function relationship of the peptides, particularly with regard to (i) increasing or decreasing hydrophobicity, (ii) positive/negative charge density, and (iii) altering the arc of the hydrophobic and hydrophilic faces of the peptides. The peptides shown in Table 10 (below) will be used to illustrate the results of the study.


TABLE 10
Predicted Binding of Select Peptides to RelB
RelB
Binding E
SEQ ID
RP#
Sequence
(kCal/mol)*
Formula
NO:
RP-182
KFRKAFKRFF
−944.8
XI
121
RP-166
FFEHFWKEFN
−1,044.8
X
112
RP-113
FFFRFFFEFQ
−1,208.9
II
39
RP-289
AKKKAKKKAK
−431.6
V
232
RP-387
AAKKAAKKAK
−338.3
X
173
NF-CONTR2
IESKRRKKKP
−476.6
N/A
382
NF-CONTR3
APGPGDGGTA
−621.1
N/A
383
*The lower the energy value, the greater affinity the ligand possesses for the binding site on the target protein.

A structural model of the RelB subunit of NF-kB is shown in FIG. 1. Amino acids with the dimerization site are shaded to indicate their hydrophobic or hydrophilic character. In particular, the amino acid residues colored magenta are hydrophilic, while the amino acid residues colored cyan are hydrophobic. Given the distinct locations of the hydrophilic and hydrophobic amino acid residues within the binding pocket of the dimerization domain, it is evident that striapathic peptides having an amphipathic secondary structure have the potential to bind site-specifically to the dimerization domain binding pocket.

The secondary structure of RP-182 (SEQ ID NO: 121) and its binding to RelB (SEQ ID NO: 367) is modeled in FIG. 2. As can be seen in the panels on the right, RP-182's predicted secondary structure has distinct hydrophobic and hydrophilic sides that comprise approximately equal facial arcs (see also FIG. 9) and are of high volume. Overall, the structure of RP-182 possesses high hydrophobicity and high cationicity (with a total of five cationic amino acid residues). These characteristics of RP-182 are summarized in Table 11, below. Based on the structural modeling, RP-182 binds with high affinity to the RelB dimerization domain binding pocket, with an estimated binding energy of −944.8 kcal/mol.

The secondary structure of RP-166 (SEQ ID NO: 112) and its binding to RelB (SEQ ID NO: 367) is modeled in FIG. 3. As can be seen in the panels on the right, RP-166's predicted secondary structure also has distinct hydrophobic and hydrophilic sides that comprise approximately equal facial arcs (see also FIG. 9). These characteristics are not surprising, as the striapathic region of RP-166 has a modular structure that is identical (albeit reversed) to that of RP-182's (compare Formulas X and XI). As with RP-182, the hydrophobic and hydrophilic surfaces of RP-166 are of high volume, but RP-166 has a greater ratio of hydrophobic volume to hydrophilic volume as compared to RP-182. In addition, the cationicity of RP-166 is significantly reduced relative to that of RP-182, since RP-166 has an equal number of cationic amino acid residues and anionic amino acid residues. These characteristics of RP-166 are summarized in Table 11, below. Based on the structural modeling, RP-166 binds to the RelB dimerization domain binding pocket with even higher affinity than RP-182, having an estimated binding energy of −1,044.8 kcal/mol.

The secondary structure of RP-113 (SEQ ID NO: 39) and its binding to RelB (SEQ ID NO: 367) is modeled in FIG. 4. As can be seen in the panels on the right, RP-113's predicted secondary structure also has distinct hydrophobic and hydrophilic sides, but the hydrophobic side comprises a much larger facial arc than the hydrophilic side. As shown in FIG. 9, the facial arc of the polar side of RP-113 is only 60°, while the facial are of the non-polar side is 300°. Consistent with this shift toward a larger hydrophobic surface, RP-113 has a larger hydrophobic volume than either RP-182 or RP-166, as well as a significantly larger ratio of hydrophobic to hydrophilic volume. See Table 11, below. Like RP-166, the cationicity of RP-113 is significantly reduced relative to that of RP-182, since RP-113 has an equal number of cationic amino acid residues and anionic amino acid residues. Based on the structural modeling, RP-113 binds to the RelB dimerization domain binding pocket with one of the highest affinities predicted for the peptides of the invention, having an estimated binding energy of −1,208.9 kcal/mol.

The secondary structure of RP-387 (SEQ ID NO: 173) and its binding to RelB (SEQ ID NO: 367) is modeled in FIG. 5. As can be seen in the panels on the right, RP-387's predicted secondary structure has distinct hydrophobic and hydrophilic sides. However, in contrast to RP-113, the hydrophilic side of RP-387 comprises a much larger facial arc than the hydrophobic side. As shown in FIG. 10, the facial are of the polar side of RP-387 is 245°, while the facial arc of the non-polar side is 115°. Consistent with this shift toward a larger hydrophilic surface, RP-387 has a smaller hydrophobic volume than any of RP-182, RP-166, and RP-113, as well as a significantly smaller ratio of hydrophobic to hydrophilic volume. See Table 11, below. With regard to cationicity, RP-387 is similar to RP-182, having a total of five cationic amino acid residues. Based on the structural modeling. RP-387 binds to the RelB dimerization domain binding pocket, but is does so relatively poorly, having an estimated binding energy of only −338.3 kcal/mol.

The secondary structure of RP-289 (SEQ ID NO: 232) and its binding to RelB (SEQ ID NO: 367) is modeled in FIG. 6. As can be seen in the panels on the right, RP-289's predicted secondary structure has distinct hydrophobic and hydrophilic sides. However. RP-289's hydrophobic side is one of the smallest of the peptides screened. As shown in FIG. 9, the facial arc of the polar side of RP-289 is 290°, while the facial arc of the non-polar side is only 70°. Of the peptides listed in Table 11, RP-289 has the smallest hydrophobic volume and the smallest ratio of hydrophobic to hydrophilic volume. RP-289 also has the highest cationicity of the peptides listed in Table 11, having a total of seven cationic amino acid residues. Based on the structural modeling, RP-289 binds to the RelB dimerization domain, though comparatively much more weakly than RP-182, RP-166, and RP-113, having an estimated binding energy of only −431.6 kcal/mol.

Tables 10 and 11 also identify two control peptides, NF-CONTR2 and NF-CONTR3, which are fragments of the RelB subunit of NF-kB. The sequences of NF-CONTR2 and NF-CONTR3 do not conform to any of structural Formulas I-LIII. The secondary structure of NF-CONTR2 (SEQ ID NO: 382) and its binding to RelB (SEQ ID NO: 367) is modeled in FIG. 7. The secondary structure of NF-CONTR3 (SEQ ID NO: 383) and its binding to RelB (SEQ ID NO: 367) is modeled in FIG. 8. Neither peptide is predicted to adopt a clearly amphipathic secondary structure throughout the length of the peptide. Moreover, although the ClusPro™ algorithm identifies a binding interaction between each of NF-CONTR2 and NF-CONTR3 and RelB, the binding energies are not very strong and neither peptide displays a preference for binding to the RelB dimerization domain binding pocket.


TABLE 11
Physical Characteristics of Select Peptides
HPB
SEQ
RelB
Vol/
ID
Binding
HPL
HPB
HPL
tH
tH
tH HPB/
RP#
Sequence
NO:
Energy
(+)
(−)
Vol
Vol
Vol
HPL
HPB
tH HPL
182
KFRKAFKRFF
121
−944.8
6
1
696.9
659.8
0.95
−50.8
16.4
−0.32
166
FFEHFWKEFN
112
−1,044.8
3
3
637.7
775.0
1.22
−33.0
16.7
−0.51
113
FFFRFFFEFQ
39
−1,208.9
2
2
414.5
1030.4
2.49
−23.5
25.9
−1.10
289
AKKKAKKKAK
232
431.6
8
1
896.8
213.3
0.24
−61.6
4.8
−0.08
387
AAKKAAKKAK
173
−338.3
6
1
640.5
355.5
0.55
−44.0
8.0
−0.18
NF-C2
IESKRRKKKP
382
−476.6
7
2
954.9
297.4
0.31
−66.8
3.5
−0.05
NF-C3
APGPGDGGTA
383
−621.1
1
1
115.1
665.7
5.78
−9.2
8.0
−0.87
*Binding energies are in kcal/mol.
Volumes are in cubic angstroms.
HPL means hydrophilic;
HPB means hydrophobic.
“tH” is the total hydrophobicity (in kcal/mol), as defined by Engleman et al. (1986),
“Identifying nonpolar transbilayer helices in amino acid sequences of membrane proteins,” Annu. Rev. Biophys. Bioeng. 15: 321-53.

FIGS. 1 through 10 and Table 11 reveal some important aspects of the structure-function relationship for the peptides of the invention. First, all of the peptides that are predicted to bind the RelB dimerization domain binding pocket have an amphipathic secondary structure. Second, greater hydrophobic volume, a greater ratio of hydrophobic to hydrophilic volume, and a greater hydrophobic arc are all associated with increased affinity for the binding pocket of the RelB dimerization domain. Third, increased cationicity is associated with decreased binding affinity for the binding pocket of the RelB dimerization domain.

Table 4, which lists some “all hydrophilic” variants of the Class I peptides, appears to potentially refute the conclusion that increased cationicity is associated with decreased binding affinity for the binding pocket of the RelB dimerization domain. In each of the peptides in Table 4, the hydrophobic residues of a Class I, Formula II peptide have been replaced with a single type of hydrophilic residue. Significantly, RP-173 (HHHRHHHEHQ; SEQ ID NO: 99) and RP-195 (RRRRRRRERQ; SEQ ID NO: 100) both have a high affinity for the binding pocket of the RelB dimerization domain (−1,002.2 and −855.2 kcal/mol, respectively), despite have eight amino acid residues that generally have a cationic charge in solution. Because both histidine and arginine have large side chains, a potential explanation for their high RelB binding affinities is that the uncharged hydrocarbon groups in the side chains provide some hydrophobicity that would otherwise have been lost by switching from a hydrophobic residue to a hydrophilic residue. In addition, when bound to RelB, some of the histidine and arginine residues may adopt an uncharged state. Table 4 therefore sheds further light on the structure-function relationship of the peptides of the invention by indicating that histidine and arginine can function in a quasi-hydrophobic capacity, at least with regard to the binding affinities of peptides for the RelB dimerization domain binding pocket. Accordingly, in some peptides of the invention, it can be energetically advantageous to place a histidine or arginine adjacent to a hydrophobic module that is made up of one or two hydrophobic amino acid residues.

Example 3: RelB Amino Acid Residues Involved in Peptide Binding

A model of the amino acid residues that line the binding pocket of the RelB dimerization domain is shown in FIG. 11. The model shows that Glu-298, Asp-330, and His-332 are key hydrophilic amino acid residues that line the binding pocket, while Tyr-300, Leu-301, Leu-302, and Leu-371 are important hydrophobic residues. The same model, with the addition of a stick diagram of the RP-182 peptide (SEQ ID NO: 121) is shown in FIG. 12. The dotted lines in FIG. 12 show ionic bonds between (1) Lys-7 of RP-183 and Asp-330 of RelB, and (2) Lys-4 of RP-183 and Glu-298 of RelB. Further stabilizing the interaction is an intra-ionic bond formed between Arg-8 of RP-183 and the carboxy terminal Lys-10 of RP-183. In addition to the ionic binds, there are numerous Van der Waals interactions. For the sake of clarity, only that of Phe-9 of RP-182 with Leu-371 of Rel-B is shown. However, the other hydrophobic amino acid residues on the hydrophobic face of RP-183 interact with the hydrophobic “floor” of the cleft of dimerization site of Rel-B.

An analysis of the ionic and Van der Waals interactions involved with the binding of different peptides of the invention has revealed that the peptides bind to a subset of the RelB amino acid residues selected from the group consisting of Leu-281, Ile-283, Cys-284, Glu-298, Tyr-300, Leu-301, Leu-302, Cys-303, Ile-311, Ser-312, Ala-329, Asp-330, Val-331, His-332, Gln-334, and Leu-371. See Table 13, below. Tyr-300, Leu-302, and His-332 are designated in the literature as being critical for dimerization. The amino acids most critical to binding by peptides of the invention include Glu-298, Tyr-300. Leu-302, Asp-330, Gln-334, and Leu-371.

Example 4: Binding of Peptides to Protein Targets Other than RelB

A subset of the peptides shown in Tables 3-9 were further evaluated in silico to determine whether they bind to signaling proteins involved in the inflammatory response other than RelB. In doing so, it was discovered the dimerization cleft of the RelB subunit of NF-kB has structural parallels in a number of other signaling molecules. Consistent with these structural parallels, the peptides of the invention are predicted (by the ClusPro™ algorithm) to bind with high affinity to important signaling molecules in the inflammatory cascade, including: TGFβ (NCBI Acc. No. NP_000651.3; SEQ ID NO: 368); Notch1 (GenBank Acc. No. AAG33848.1; SEQ ID NO: 369); Wnt8R (NCBI Acc. No. XP_005214377.1; SEQ ID NO: 370); TRAIL (GenBank Acc. No. EAW78466.1; SEQ ID NO: 371); IL6R (NCBI Acc. No. NP_786943.1; SEQ ID NO: 372); IL10R (NCBI Acc. No. NP_001549.2; SEQ ID NO: 373); EGFR (GenBank Acc. No. AAR85273.1; SEQ ID NO: 374); and CDK6 (NCBI Acc. No. NP_001250.1; SEQ ID NO: 375). Representative peptides of the invention and the predicted binding energies between the peptides and each of these signaling molecules is shown in Tables 12A and 12B, below.


TABLE 12A
Predicted Binding of Select Peptides to
Different Inflammatory Targets
SEQ ID
RP#
Sequence
NO:
RelB
TGFβ
NOTCH1
WNT8R
TRAIL
185
FFKKFFKKFK
123
920.6
−880.1
−817.7
−747.2
−904.5
186
KFKKFFKKFF
124
−919.6
−846.0
−887.7
−739.1
−884.3
183
FFRKFAKRFK
122
−933.2
−878.9
−890.8
−763.1
−938.8
182
KFRKAFKRFF
121
−944.8
−851.8
−1,096.3
−733.7
−938.8
118
FFFRFFFNFN
44
−1,139.9
−1,074.7
−1,032.4
−990.9
−995.4
394
NFNFFFRFFF
33
−1,286.6
−1,002.6
−1,059.6
−971.2
−943.8
389
FRFKFA
257
−1,009.8
−878.4
−846.4
−804.5
−916.8
390
FRFKFKF
256
−1,083.3
−933.2
−1,005.3
−871.0
−1,014.4
391
FRFKFKFR
254
−1,190.8
−987.5
−1,005.4
−897.9
−1,049.2
392
RFQFKFRF
255
−1,170.3
−943.2
−923.1
−853.8
−1,039.6
387
AAKKAAKKAK
173
−301.6
−397.7
−385.5
−394.9
−397.7
*All binding affinities are in kcal/mol.


TABLE 12A
Predicted Binding of Select Peptides to
Different Inflammatory Targets
SEQ ID
RP#
Sequence
NO:
RelB
EGFR
IL6R
IL10R
CDK6
185
FFKKFFKKFK
123
−920.6
−785.4
−747.5
−756.3
−753.9
186
KFKKFFKKFF
124
−919.6
−866.3
−755.0
−742.0
−718.1
183
FFRKFAKRFK
122
−933.2
−795.6
−696.7
−738.6
−783.0
182
KFRKAFKRFF
121
−944.8
−853.8
−784.5
−785.9
−781.5
118
FFFRFFFNFN
44
−1,139.9
−1,039.4
−1,074.8
−881.4
−1,020.8
394
NFNFFFRFFF
33
−1,286.6
−1,061.4
−1,069.9
−850.8
−1,075.3
389
FRFKFA
257
−1,009.8
−896.0
−812.3
−779.2
−900.5
390
FRFKFKF
256
−1,083.3
−1,036.3
−952.2
−876.2
−861.1
391
FRFKFKFR
254
−1,190.8
−1,024.9
−957.6
−882.3
−899.9
392
RFQFKFRF
255
−1,170.3
−1,010.4
−1,052.3
−901.7
−870.0
387
AAKKAAKKAK
173
−301.6
−395.9
−342.0
−338.1
−351.4

The data reveals that the strength of binding to RelB is highly correlated with the strength of binding to the various inflammatory targets. In other words, peptides that are predicted to bind with high affinity to RelB are likewise predicted to bind with high affinity to TGFβ, Notch1, Wnt8R, TRAIL, EGFR, IL6R, and IL10R.

A closer evaluation of the predicted binding interactions between the peptides of the invention and each of TGFβ, Notch1, Wnt8R, TRAIL, EGFR, IL6R, and IL10R reveals that the peptides not only bind with high affinity, but also bind to functionally critical sites on the targets. For example, peptides of the invention are predicted to bind to the receptor-binding site on TGFβ, the calcium-binding site on Notch1, the Wnt8-binding site on Wnt8R, the receptor-binding site on TRAIL, the IL6-binding site on IL6R, the IL10-binding site on IL10R, and the general ligand-binding site on EGFR. A non-exhaustive list of amino acid residues in each of these targets that are bound by the peptides of the invention is shown in Table 13.


TABLE 13
Amino Acid Residues in Target Proteins Contacted
by Peptides of the Invention
SEQ ID
Target
NO:
AA Residue Contacts
Most Critical AAs
RelB
367
Leu-281, Ile-283, Cys-284, Glu-298, Tyr-300,
Glu-298, Tyr-300, Leu-
Leu-301, Leu-302, Cys-303, Ile-311, Ser-312,
302, Asp-330, Gln-334,
Ala-329, Asp-330, Val-331, His-332, Gln-334,
Leu-371
Leu-371
TGFβ
368
Leu-20, Ile-22, Phe-24, Asp-27, Leu-28, Trp-30,
Asp-27, Leu-28, Trp-30,
Trp-32, Tyr-39, Phe-43, Pro-80, Leu-83, Leu-101,
Trp-32
Ser-112
Notch1
369
Phe-1520, Gln-1523, Arg-1524, Glu-1526, Ala-
Phe-1520, Trp-1557,
1553, Glu-1556, Trp-1557, Cys-1562, His-1602,
Cys-1562, Phe-1703
Arg-1684, Gln-1685, Cys-1686, Ser-1691, Cys-
1693, Phe-1694, Phe-1703
Wnt8R
370
Tyr-52, Gln-56, Phe-57, Asn-58, Met-91, Tyr-
Tyr-52, Phe-57, Tyr-100,
100, Lys-101, Pro-103, Pro-105, Pro-106, Arg-
Asp-145
137, Asp-145
TRAIL
371
Ala-123, His-161, Ser-162, Phe-163, Tyr-183,
Phe-163, Tyr-243, Glu-
Tyr-185, Tyr-243, His-270, Glu-271, Phe-274
271, Phe-278
Phe-278, Leu-279, Val-280
IL6R
372
Leu-108, Glu-140, Pro-162, Phe-229, Tyr-230,
Glu-140, Phe-229, Tyr-
Phe-279
230, Phe-279
IL10R
373
Leu-41, Arg-42, Tyr-43, Ile-45, Glu-46, Ser-47,
Tyr-43, Ile-45, Glu-46,
Trp-48, Arg-76, Arg-78
Trp-48
EGFR
374
Leu-10, Thr-40, Trp-41, Asp-48, Phe-51, Leu-63,
Trp-41, Asp-48, Phe-51,
His-66, Asp-68, Leu-88, Tyr-101
Asp-68, Tyr-101,
CDK6
375
Val-142, Arg-144, Asp-145, Ser-171, Val-180,
Asp-145, Val-180, Tyr-
Val-181, Leu-183, Arg-186, Val-190, Gln-193,
196
Tyr-196, Val-200
HMT
376
Tyr-16, Glu-48, Tyr-50, Leu-51, Phe-52, Asn-69
Tyr-16, Glu-48, Tyr-50,
Leu-51, Phe-52, Asn-69
CD47
377
Tyr-37, Thr-49, Phe-50, Asp-51, Ala-53, Glu-97,
Tyr-37, Glu-97, Glu-100,
Val-98, Glu-100, Leu-101, Thr-102, Glu-104,
Leu-101, Glu-104, Glu-
Glu-106, Gly-107
106
SIRP-α
378
Tyr-50, Gln-52, Pro-58, Ser-66, Thr-67, Ser-77
Tyr-50, Gln-52, Ser-66,
Thr-67
CD206
379
Phe-708, Thr-709, Trp-710, Pro-714. Glu-719,
Phe-708, Trp-710, Trp-
Asn-720, Trp-721, Ala-722, Glu-725, Tyr-729,
721, Glu-725, Tyr-729,
Glu-733, Asn-747, Asp-748, Ser-1691, Cys-1693,
Glu-733
Phe-1694, Phe-1703
TGM2
380
Cys-277, His-335, Asp-358
Cys-277, His-335, Asp-
358

Given the large number of immunologically important signaling proteins that are targeted by the peptides of the invention, the data suggests that the peptides act in a pleiotropic manner, making many different interactions that sum together to create a broad anti-inflammatory response. This may make possible a reduction in disease conditions without the toxicity observed in the use of more highly-targeted chemotherapeutic agents.

Example 5: Binding of Peptides to Histone Modifying Enzymes and Ribonuclease Reductase

A number of the peptides of the invention were observed to share structural characteristics of the N-terminal regions of histones. Accordingly, representative peptides were evaluated in silico for their ability to bind to histone modification enzymes. In this manner, it was discovered that the peptides of the invention have high binding affinity for histone methyl transferase (HMT)(NCBI Acc. No. NP_048968.1; SEQ ID NO: 376), binding close to the active site of the enzyme. Predicted binding energies of select peptides of the invention for HMT, calculated using the ClusPro™ algorithm, are shown in Table 14. Again, the predicted binding energies correlate well with the predicted energies for binding RelB.


TABLE 14
Binding Affinities of Select Peptides
to HMT, MKK7, and RNR
SEQ ID
RP#
Sequence
NO:
RelB
HMT
185
FFKKFFKKFK
123
−920.6
−846.4
186
KFKKFFKKFF
124
−919.6
−795.7
183
FFRKFAKRFK
122
−933.2
−839.4
182
KFRKAFKRFF
121
−944.8
−826.6
118
FFFRFFFNFN
44
−1,139.9
−1,000.2
394
NFNFFFRFFF
33
−1,286.6
−998.4
389
FRFKFA
257
−1,009.8
−836.8
390
FRFKFKF
256
−1,083.3
−906.6
391
FRFKFKFR
254
−1,190.8
−949.2
392
RFQFKFRF
255
−1,170.3
−962.2
387
AAKKAAKKAK
173
−301.6
−334.5
*All binding affinities are in kcal/mol.

A model of Histone Methyl Transferase (HMT) bound by RP-182 is shown in FIG. 13. The orange amino acids are the active site of the histone methyl transferase enzyme. Inhibition of methyl transferase activity by RP-182 is expected since RP-182 binds to at least one residue of the active site, in a manner that appears to obstruct access to the active site. A non-exhaustive list of amino acid residues in HMT that are bound by the peptides of the invention is shown in Table 13, above.

Peptides of the invention are also observed to display strong predicted affinities to MAP kinase kinase 7 (MKK7; SEQ ID NO: 166), a member of the mitogen-activated protein kinase kinase family involved in signal transduction mediating cell responses to proinflammatory cytokines, and therefore likely involved in peptides' anti-inflammatory activity. The predicted affinity of e.g. RP-182 for MKK7 is −738.2 kcals/mol.

In addition, peptides of the invention were observed to display substantial predicted affinities to ribonuclease reductase (RNR; SEQ ID NO: 168) also known as ribonucleoside diphosphate reductase. This is an enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides. Deoxyribonucleotides in turn are used in the synthesis of DNA. The reaction catalyzed by RNR is strictly conserved in all living organisms. Furthermore, RNR plays a critical role in regulating the total rate of DNA synthesis, so that DNA to cell mass is maintained at a constant ratio during cell division and DNA repair. A somewhat unusual feature of the RNR enzyme is that it catalyzes a reaction that proceeds via a free radical mechanism of action. The substrates for RNR are ADP, GDP, CDP and UDP. dTDP (deoxythymidine diphosphate) is synthesized by another enzyme (thymidylate kinase) from dTMP (deoxythymidine monophosphate). The predicted affinity of e.g. RP-182 for RNR is −814.0 kcals/mol.

Example 6: Binding of Peptides to Targets Associated with Macrophage Activation

Peptides of the invention are also predicted to interact with several proteins relevant to macrophage activity and apoptosis, properties associated with inflammation and with tumor genesis and metastasis. Targets identified to date include CD47, SIRP-α, CD206, TGM2, LEGUMAIN, DC-SIGN, CSF1, CSF1R, and IL34.

CD47 (or “Cluster of Differentiation 47”), also known as integrin associated protein (IAP), is a transmembrane protein that belongs to the immunoglobulin superfamily. CD47 protein partners with membrane-bound cellular adhesion receptors known as integrins and also binds the ligands thrombospondin-1 (TSP-1) and signal-regulatory protein alpha (SIRP-α). CD47 is involved in a range of cellular processes, including apoptosis, proliferation, adhesion, and migration. Furthermore, it plays a key role in immune and angiogenic responses. CD47 is expressed in many types of human cells and has been found to be overexpressed in many different types of tumors. The overexpression of CD47 has received considerable attention as a possible protective agent for human cancers. By binding to SIRP-α on the surface of macrophages. CD47 is believed to send a “don't eat me” signal that disables the macrophages from attacking the cancer cell.

CD206 and TGM2 have likewise been identified as potentially important regulators of macrophage activity. CD206 is a C-type lectin, primarily present on the surface of macrophages and dendritic cells. It is the first member of a family of endocytic receptors that includes Endo 180 (CD280), M-type PLA2R, and DEC-205 (CD205). The receptor recognizes terminal mannose. N-acetylglucosamine, and fucose residues that make up glycans, which are attached to proteins found on the surface of some microorganisms. Accordingly, the CD206 receptor appears to play a role in both the innate and adaptive immune systems. In addition, tumor-associated macrophages may use CD206 to ingest collagen, yielding degradation products capable of nourishing both themselves and tumor cells, and weakening collagen binding of tumor cells so as to encourage metastasis.

TGM2 belongs to a family of enzymes that catalyze the calcium-dependent translational modification of proteins. The family members are found both intracellularly and extracellularly. TGM2 is unique in the family because of its multi-functionality and specialized structure, which includes four distinct domains: an N-terminal β-sandwich that contains fibronectin and integrin binding sites; a catalytic core that contains the catalytic triad for acyl-transfer reactions (Cys-277, His-335, and Asp-358); and two C-terminal β-barrel domains, with the second having a phospholipase-binding sequence. TGM2 has been implicated as a regulator of extracellular matrix functions, including cell adhesion and migration, cellular growth and differentiation, apoptosis, tumor growth, and wound healing. Although TGM2 is ubiquitously expressed, it is most highly expressed in M2 macrophages. Furthermore, increased TGM2 levels are associated with scleroderma, lung and kidney fibrosis, worsening symptoms for diabetes, arthritis, and EAE, and poor outcomes in a number of different cancers, all of which can be linked to M2 macrophages.

Predicted binding energies of select peptides of the invention for CD47 (NCBI Acc. No. XP_005247966.1; SEQ ID NO: 377), SIRP-α (GenBank Acc. No. AAH26692.1; SEQ ID NO: 378), CD206 (NCBI Acc. No. NP_002429.1; SEQ ID NO: 379), and TGM2 (GenBank Acc. No. AAB95430.1; SEQ ID NO: 380) calculated using the ClusPro™ algorithm, are shown in Table 15. As with the other targets discussed above, the predicted binding energies correlate well with the predicted energies for binding RelB.

LEGUMAIN is a protein that in humans is encoded by the LGMN gene. This gene encodes a cysteine protease, legumain that has a strict specificity for hydrolysis of asparaginyl bonds. This enzyme may be involved in the processing of bacterial peptides and endogenous proteins for MHC class II presentation in the lysosomal/endosomal systems. Enzyme activation is triggered by acidic pH and appears to be autocatalytic. Protein expression occurs after monocytes differentiate into dendritic cells. A fully mature, active enzyme is produced following lipopolysaccharide expression in mature dendritic cells. Overexpression of this gene may be associated with the majority of solid tumor types. LEGUMAIN is also overexpressed in M2 macrophages, and inhibition of its activity by the disclosed peptides is expected to downregulate M2-activated macrophages.

DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) also known as CD209 (Cluster of Differentiation 209) is a protein that in humans is encoded by the CD209 gene. DC-SIGN is a C-type lectin receptor present on the surface of both macrophages and dendritic cells. DC-SIGN on macrophages recognizes and binds to mannose type carbohydrates, a class of pathogen associated molecular patterns PAMPs commonly found on viruses, bacteria and fungi. This binding interaction activates phagocytosis. On myeloid and pre-plasmacytoid dendritic cells DC-SIGN mediates dendritic cell rolling interactions with blood endothelium and activation of CD4+ T cells, as well as recognition of pathogen haptens. DC-SIGN is significantly overexpressed in M2 macrophages, and inhibition of its activity by the disclosed peptides is expected to downregulate M2-activated macrophages.


TABLE 15
Binding Affinities of Select Peptides to CD47,
SIRP-α, CD206, and TGM2
RP#
Sequence
SEQ ID NO:
RelB
SIRP-α
CD47
CD206
TGM2
185
FFKKFFKKFK
123
−920.6
−799.2
−639.3
−807.1
−827.2
186
KFKKFFKKFF
124
−919.6
−711.8
−637.4
−881.3
−885.3
183
FFRKFAKRFK
122
−933.2
−834.2
−658.1
−786.7
−860.7
182
KFRKAFKRFF
121
−944.8
−733.1
−723.1
−844.5
−869.1
118
FFFRFFFNFN
44
−1,139.9
−805.2
−751.5
−1,048.7
n/a
394
NFNFFFRFFF
33
−1,286.6
−854.2
−751.5
−986.6
n/a
389
FRFKFA
257
−1,009.8
−934.6
−688.3
−861.9
n/a
390
FRFKFKF
256
−1,083.3
−887.2
−783.5
−978.1
n/a
391
FRFKFKFR
254
−1,190.8
−932.1
−790.1
−941.3
n/a
392
RFQFKFRF
255
−1,170.3
−982.5
−792.1
−981.6
n/a
387
AAKKAAKKAK
173
−301.6
−392.3
−308.7
−416.6
n/a
*All binding affinities are in kcal/mol.

FIG. 14 (left panel) shows a model of the ecto-domain of a CD47 dimer (top view) (SEQ ID NO: 377), with magenta- and cyan-colored surfaces representing the polar and non-polar amino acids, respectively, that are involved in the binding of CD47 to the SIRP-α receptor. FIG. 14 (right panel) is a model of the ecto-domain of the CD47 dimer when bound by RP-183 (SEQ ID NO: 121). Based on this predicted interaction between RP-183 and CD47, peptides of the invention are expected to block the interaction between CD47 and SIRP-α.

FIG. 15 shows a model of a SIRP-α dimer (SEQ ID NO: 378), with magenta- and cyan-colored surfaces representing the polar and non-polar amino acids involved in its binding to CD47 (see left-most dimer). In a slightly-skewed view of the same SIRP-α dimer bound by RP-183 (SEQ ID NO: 122) (see right-most dimer), it can be seen that RP-183 binds tightly to the amino acids involved in binding to the CD47 receptor. It therefore appears that RP-183 (and other peptides of the invention) block the interaction between CD47 and SIRP-α by two distinct mechanisms, binding to the corresponding binding sites in both CD47 and SIRP-α. Thus, predicted activities associated with the peptides of the invention include thwarting of an important defense mechanism for cancer cells.

Peptides of the invention are also predicted to block key sites on the CD206 receptor subunit. FIG. 16 shows a model of CD206 (SEQ ID NO: 379) bound by RP-182 (SEQ ID NO: 121). The cyan-colored tyrosine residue on the bend region of CD206 (left-most molecule) forms a planar, hydrophobic stacking interactions with the mannose ligands on the surface of target cells. The magenta colored amino acids are acidic residues that help chelate the required calcium ion necessary for stable interactions with the mannose receptor. The RP-182 peptide (seen in mesh on the right-most molecule) blocks activity by interacting with both of these key sites on the receptor subunit. Peptides of the invention are therefore expected to reduce the viability of M2 macrophages, which has been experimentally confirmed (as set forth below).

Furthermore, peptides of the invention are predicted to block the active site of TGM2. FIG. 17 (left panel) shows a model of TGM2 (SEQ ID NO: 380) with the active site residues highlighted in blue. FIG. 17 (right panel) shows the same model of TGM2 bound by RP-182 (SEQ ID NO: 121), which is colored magenta. As can be seen, RP-182 is predicted to bind to TGM2 in a manner that completely covers the active site, thereby obstructing substrate access and inhibiting TGM2 function. Significantly, decreased levels of TGM2 is associated with reduced NF-kB activation, so the interaction of the polypeptides of the invention with TGM2 would appear to reinforce and/or augment their suppression of NF-kB activity.

Non-exhaustive lists of specific amino acid residues in CD47, SIRP-α, CD206, and TGM2 that are bound by the peptides of the invention are shown in Table 13, above.

Example 7: Binding of Peptides to Checkpoint Inhibitors and Related Targets

It has also been observed that peptides of the present invention display substantial affinity to checkpoint inhibitor proteins and their ligands. Such proteins, including cytotoxic T-lymphocyte antigen 4 (CTLA-4), PD-1, and other inhibitory coreceptors, expressed on the surface of effector immune cells, when activated appear to exhaust the activity of the immune cells, serving as immune checkpoints in order to prevent uncontrolled immune reactions. Tumor cells often express ligands to the checkpoint inhibitors, e.g. PD-L1 and PD-L2, attenuating the capacity of the immune system to attack the tumor.

In particular, programmed cell death protein 1, also known as PD-1 and CD279 (cluster of differentiation 279), is a protein that in humans is encoded by the PDCD1 gene. PD-1 is a cell surface receptor that belongs to the immunoglobulin superfamily and is expressed on T cells and pro-B cells. PD-1 binds two ligands, PD-L1 and PD-L2. PD-1, functioning as an immune checkpoint plays an important role in downregulating the immune system by preventing the activation of T-cells, which in turn reduces autoimmunity and promotes self-tolerance. The inhibitory effect of PD-1 is accomplished through a dual mechanism of promoting apoptosis (programmed cell death) in antigen specific T-cells in lymph nodes while simultaneously reducing apoptosis in regulatory T cells (suppressor T cells).

Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the CD274 gene. Programmed death-ligand 1 (PD-L1) is a 40 kDa type I transmembrane protein that has been speculated to play a major role in suppressing the immune system during particular events such as pregnancy, tissue allografts, autoimmune disease and other disease states such as hepatitis. Normally the immune system reacts to foreign antigens where there is some accumulation in the lymph nodes or spleen that triggers a proliferation of antigen-specific CD8+ T cell. The formation of PD-1 receptor/PD-L1 or B7.1 receptor/PD-L1 ligand complex transmits an inhibitory signal which reduces the proliferation of these CD8+ T cells at the lymph nodes and supplementary to that PD-1 is also able to control the accumulation of foreign antigen specific T cells in the lymph nodes through apoptosis which is further mediated by a lower regulation of the gene Bcl-2.

As illustrations of the binding of peptides of the present invention with checkpoint inhibitors and their ligands, the predicted affinity of RP-182 to PD-1 is −742.9, and that of RP-621 is −1,008.8. The affinity of RP-182 to PD-L1 is −677.4, and that of RP-621 to PD-L1 is −1,010.6. As with inflammatory targets, there is a striking correlation among predicted affinities to several other checkpoint inhibitors and their ligands, as well as other proteins known to play a role in modulating the immune apparatus. These include: TIM-1 (believed to play a role in T-helper cell development: predicted affinity to RP-182, −850.1); CTLA-4 (checkpoint inhibitor: predicted affinity to RP-182, −663.2); ADORA2a (modulates activity of neutrophils and mast cells: predicted affinity to RP-182, −938.7); OX40 (secondary co-stimulatory immune checkpoint: predicted affinity to RP-182, −759.9); IDO (immune checkpoint: predicted affinity to RP-182, −934.0); LAG-3 (immune checkpoint receptor: predicted affinity to RP-182, −873.1); CD73 (enzyme limiting T cell activity through adenosine receptor signaling: predicted affinity of CD73-I to RP-182, −808.7; predicted affinity of CD73-II to RP-182, −949.1); Arginase-1 (blocks activity of cytotoxic T lymphocytes: predicted affinity to RP-182, −984.2); Colony Stimulating Factor 1 (blockade shown to upregulate checkpoint molecules, as well as reprogramming macrophage responses; predicted affinity of CSF1 to RP-182, −854.7; predicted affinity of CSF1D to RP-182, −847.1; predicted affinity of CSF1R to RP-182, −774.1); and IL34 (also activates CSF1R; predicted affinity to RP-182, −828.5).

Example 8: Binding of Peptides to MKK7

Dual specificity mitogen-activated protein kinase kinase 7, also known as MAP kinase kinase 7 or MKK7, is an enzyme that in humans is encoded by the MAP2K7 gene. This protein is a member of the mitogen-activated protein kinase kinase family. The MKK7 protein exists as six different isoforms with three possible N-termini (α, β, and γ isoforms) and two possible C-termini (1 and 2 isoforms). MKK7 is involved in signal transduction mediating the cell responses to proinflammatory cytokines, and environmental stresses. This kinase specifically activates MAPK8/JNK1 and MAPK9/JNK2, and this kinase itself is phosphorylated and activated by MAP kinase kinase kinases including MAP3K1/MEKK1, MAP3K2/MEKK2, MAP3K3/MEKK5, and MAP4K2/GCK.

Example 9: Binding of Peptides to Serum Albumin

It is well-known that the most abundant protein in the circulation is serum albumin. It is also known that solid tumors will take up serum albumin into their cells (through the process of pinocytosis) and use it as an energy source. Therefore, peptides of the invention were evaluated in silico for their ability to bind to human serum albumin (HSA)(NCBI Acc. No. NP_000468.1; SEQ ID NO: 381). It was discovered that peptides of the invention have the capacity to bind to HSA with high affinity. Predicted binding energies of select peptides of the invention for binding to HSA are shown in Table 16, below.


TABLE 16
Binding Affinities of Select Peptides to
Human Serum Albumin (HSA)
SEQ ID
RP#
Sequence
NO:
RelB
HSA
185
FFKKFFKKFK
123
−920.6
−880.2
186
KFKKFFKKFF
124
−919.6
−850.5
183
FFRKFAKRFK
122
−933.2
−860.1
182
KFRKAFKRFF
121
−944.8
−789.0
118
FFFRFFFNFN
44
−1,139.9
−1,064.7
394
NFNFFFRFFF
33
−1,286.6
−1,016.5
389
FRFKFA
257
−1,009.8
−904.8
390
FRFKFKF
256
−1,083.3
−1,046.0
391
FRFKFKFR
254
−1,190.8
−1,021.9
392
RFQFKFRF
255
−1,170.3
−1,037.4
387
AAKKAAKKAK
173
−301.6
−410.7
*All binding affinities are in kcal/mol.

FIG. 18 is a model of HSA (shown in green) bound by RP-183 (blue). The computational modeling has identified a number of possible peptide binding sites on HSA. Therefore, it is believed that a single HSA molecule is able to bind to multiple peptides of the invention. The binding interaction between peptides of the invention and HSA suggest that HSA could be used as an in vivo carrier of the peptides. In this manner, HSA could protect the peptides from degradation in the blood and carry the peptides to sites of action, such as sites of inflammation and/or cancer cells, thereby increasing the efficacy of the peptides.

Example 10: In Vitro Modulation of NF-kB Activity

NF-kB activity was monitored using the a 3T3-L1 preadipocyte cell line stably transformed with a Nfkb-RE/GFP construct, as described in Shen et al. (2013), “Adipocyte reporter assays: Application for identification of anti-inflammatory and antioxidant properties of mangosteen xanthones,” Mol. Nutr. Food Res. 00:1-9, the entire contents of which are incorporated herein by reference. NF-kB expressing adipocyte reporter cells were plated in DMEM in wells of a 24-well plate, at a seeding density of 5×104. On the second and third days post-plating, test peptides were individually added to the wells to a final concentration of 0.01 μM. The test peptides included RP-398 (SEQ ID NO: 155), and RP-185 (SEQ ID NO: 123). On day 4 post-plating, lipopolysaccharide was added to the medium to a final concentration of 20 ng/ml. Finally, on day 5 post-plating, the cells were harvested and a fluorescence assay performed to detect GFP expression levels.

In this experiment, NF-kB expression was reduced approximately 58% relative to control cells that were not exposed to RP-398 or RP-185 peptide.

Example 11: In Vivo Modulation of Macrophage Activity

A frequently observed phenotype associated with tumor genesis and metastasis is the polarization of macrophage cells into the “M2” transition state, in which they are in an inflammatory state. Such macrophages are among those designated as “tumor-associated macrophages” (TAMs). To determine whether the peptides of the invention could influence macrophage polarization, the following experiment was performed.

Primary bone marrow cells were collected from male C57BL/6J (The Jackson Laboratory, Bar Harbor, Me.). Mouse bone marrow macrophages were differentiated in vitro from the primary bone marrow cells by culturing in Dulbecco's minimal essential medium (DMEM) with 10% FBS and 30 ng/ml murine M-CSF (colony stimulating factor) for 6 days. At day 7, macrophages were plated into 12-well plates and cultured in DMEM (10% FBS) with (i) IL-4 peptide (20 ng/mL), (ii) INF-γ (10 ng/mL), or (iii) neither IL-4 nor INF-γ for 24 hours. After 24 hours, the media was replaced with pure DMEM and the cells were cultured for an additional 48 hours. The resulting macrophages were (i) M2-polarized, (ii) M1-polarized, or (iii) undifferentiated, respectively.

A macrophage sample containing approximately 70,000 undifferentiated macrophages per ml was incubated for 72 hours with 100 nM RP-182 (SEQ ID NO: 121). Following the incubation, a count of viable cells revealed that there were 68,000 cells per ml. Similarly, incubating M1-polarized macrophages for 72 hours with 100 nM RP-182 resulted in a viable cell count of 68.000 cells per ml. Thus, the RP-182 had little effect on the viability of M1 macrophages. In contrast, incubating M2-polarized macrophages for 72 hours with 100 nM RP-182 resulted in a viable cell count of only 20.000 cells per ml. The results indicate that RP-182 reduces the viability of M2 macrophages.

Example 12: Downregulation of Checkpoint Inhibitors and Ligands

Based on their predicted affinity to checkpoint inhibitors (e.g. PD-1) and their ligands (e.g. PD-L1 and PD-L2), the polypeptides of the invention were also evaluated to determine whether the concentration of these proteins in treated tissue would be downregulated in vivo. In one experiment, tumors in transgenic p53/KRAS mice were allowed to grow to approximately 100 m3 in volume, and the animals were then treated daily subcu for one week with either vehicle only, or 10 mg/kg RP-182, following which the animals were sacrificed and the tumors resected, formalin-fixed, and stained with antibodies to PD-1 (FIG. 19), PD-L1 and PD-L2 (FIG. 20). It is clear from the figures that both the checkpoint inhibitor PD-1 and each of its ligands PD-L1 and PD-L2 are significantly downregulated in vivo in tissue treated with peptides of the present disclosure.

Example 13: Suppression of Tumor Growth

The polypeptides of the invention were also tested for their effect on tumor growth in a mouse model of non-metastatic breast cancer. MCF-7 human non-metastatic breast cancer cells were cultured at 37° C., 5% CO2 in normal growth media. Cells were harvested at 80% to 90% confluence. Immune compromised athymic nude mice (J:NU) were divided into 2 groups (9 animals per group). All mice were injected with ˜4.5×106 MCF-7 cells which had been stained with VIVO Tracker 680 and suspended in 200 μl of PBS/Matrigel mixture. Cells were injected subcutaneously on the dorsal surface of treated animals using a 22 gauge needle fitted with a 500 μl syringe.

Animals were designated vehicle and peptide treated. The peptide treated animals were treated with the RP-397 polypeptide (SEQ ID NO: 194). Freshly prepared RP-397 peptide was dissolved in sterile saline at a concentration of 100 μM and was used to treat the animals in the peptide group. Vehicle treated animals were injected with saline buffer alone. All treatments were injected into the tumor mass two times weekly for 5 weeks using a 27 gauge needle fitted with a 1 ml syringe. Animal weights and tumor volumes were measured 3 times weekly and the fluorescence labeling was followed by VIVO Tracker 680 and IVIS Imaging. The results are shown in Table 17, below.


TABLE 17
Suppression of Tumor Growth Using RP-397
Avg. Tumor
Rate of Tumor
Body Weight
Body Weight
Weight
Growth
Before
After
Vehicle
1.5 g
63 
25.2
30.2
RP-397
0.75 g*
20*
25.1
30.1
The rate of tumor growth was measured in mm3/day.
The “*” denotes a statistically significant difference from the vehicle control.

The data shows that polypeptides of the invention can suppress tumor growth in vivo.

Example 14: Administering Peptides in Combination with Chemotherapy

Given the significant role of inflammation in tumor genesis and metastasis, as well as the known association of M2 macrophage activity with tumor development, it was anticipated that the administration of peptides of the invention could positively influence the outcomes of cancer treatment.

To test this theory, cohorts of immunocompromised (“nude”) mice were injected with ˜5×106 human triple-negative breast cancer cells (MDA-MB-231) under the upper left teat. Following this administration, one cohort received only vehicle; two of the cohorts received the chemotherapeutic agent Gemcitabine, at a q4d dose of 40 mg/kg of body weight. One of these cohorts also received RP-182 (SEQ ID NO: 121) at a daily dose of 5 mg/kg body weight; and a fourth cohort received only RP-182 at a daily dose of 5 mg/kg body weight. Beginning on day 32 of the study, in the Gemcitabine+RP-182 cohort, concentrations of RP-182 were increased to 20 mg/kg body weight. Tumor volume was assessed at various time points following initial cell administration (FIG. 21). After 50 days, the mice were sacrificed.

The data demonstrates that, as compared to treatment with Gemcitabine alone, combined treatment with Gemcitabine and polypeptides of the invention resulted in reductions in mean tumor volume. When RP-182 concentration was increased to 20 mg/kg body weight, the increase in tumor volume was essentially halted.

In a second experiment, xenografts of C42B prostate cancer cells were introduced into four cohorts of mice, and the tumors allowed to grow to approximately 100 m3 before treatment. One cohort was treated only with vehicle; a second with Docetaxel at 2.5 mg/kg body weight administered weekly; a third with RP-182 administered daily subcu at 10 mg/kg body weight; and a fourth with both Docetaxel at 2.5 mg/kg weekly and RP-182 at 10 mg/kg daily. Tumor volume was assessed at various time points following initial cell administration (FIG. 22); after 27 days, the mice were sacrificed. Similarly, the administration of RP-182 plus Docetaxel resulted in decreases in mean tumor volume compared to Docetaxel alone.

It is anticipated that the peptides of the invention will produce synergistic effects when administered with chemotherapeutic agents other than Gemcitabine and Docetaxel, as well as checkpoint inhibitor therapies and other immunotherapies. In particular, the peptides of the invention may be particularly useful when used in conjunction with recently-developed CAR-T (chimeric antigen receptor/T cell) therapies. Such therapies, while destroying tumor cells, create a very high systemic burden of dead cell material, overstimulating the immune system and creating a “cytokine storm” which can be fatal to the patient.

Embodiments

The following embodiments are provided to illustrate aspects of the present invention.

1. An anti-inflammatory composition comprising a peptide, wherein the peptide is 3 to 24 amino acid residues in length and comprises a striapathic region consisting of alternating Xm and Yn modules, wherein m and n are positive integers that identify different modules, wherein each Xm module consists of a sequence according to the formula Xma-Xmb-Xmc-Xmd-Xme, wherein Xma is selected from the group consisting of a naturally occurring hydrophilic amino acid, a non-naturally occurring hydrophilic amino acid, and a hydrophilic amino acid mimetic, and wherein Xmb, Xmc, Xmd and Xme are each individually absent or selected from the group consisting of a naturally occurring hydrophilic amino acid, a non-naturally occurring hydrophilic amino acid, and a hydrophilic amino acid mimetic, wherein each Yn module consists of a sequence according to the formula Yna-Ynb-Ync-Ynd-Yne, wherein Yna is selected from the group consisting of a naturally occurring hydrophobic amino acid, a non-naturally occurring hydrophobic amino acid, and a hydrophobic amino acid mimetic, and wherein Ynb, Ync, Ynd, and Yne are each individually absent or selected from the group consisting of a naturally occurring hydrophobic, a non-naturally occurring hydrophobic amino acid, and a hydrophobic amino acid mimetic, and wherein the peptide binds to the dimerization site on a NFkB Class II protein.

2. The anti-inflammatory composition of embodiment 1, wherein each Xm module consists of a sequence according to the formula Xma-Xmb-Xmc-Xmd, and each Yn module consists of a sequence according to the formula Yna-Ynb-Ync-Ynd.

3. The anti-inflammatory composition of embodiment 1, wherein each Xm module consists of a sequence according to the formula Xma-Xmb-Xmc, and each Yn module consists of a sequence according to the formula Yna-Ynb-Ync.

4. The anti-inflammatory composition of any one of embodiments 1 to 3, wherein the peptide also binds to human serum albumin.

5. The anti-inflammatory composition of any one of embodiments 1 to 4, wherein the striapathic region of the peptide contains at least two Xm modules (X1, X2, and X3) and at least two Yn modules (Y1, Y2, and Y3).

6. The anti-inflammatory composition of any one of embodiments 1 to 5, wherein the striapathic region of the peptide contains at least seven amino acid residues.

7. The anti-inflammatory composition of any one of embodiments 1 to 6, wherein the striapathic region of the peptide has a length of 7 to 12 amino acid residues.

8. The anti-inflammatory composition of any one of embodiments 1 to 7, wherein the striapathic region of the peptide constitutes at least 25% of the length of the peptide.

9. The anti-inflammatory composition of any one of embodiments 1 to 8, wherein the striapathic region of the peptide has an amphipathic conformation under physiological conditions.

10. The anti-inflammatory composition of embodiment 9, wherein the striapathic region of the peptide has an amphipathic 310-helical conformation, an amphipathic α-helical conformation, or an amphipathic π-helical conformation when bound to the NFkB Class II protein.

11. The anti-inflammatory composition of embodiment 10, wherein the amphipathic 310-helical, α-helical, or π-helical conformation includes a hydrophobic portion having a facial are of at least 100°.

12. The anti-inflammatory composition of any one of embodiments 1 to 11, wherein the striapathic region contains hydrophobic amino acid residues having a total volume of at least 650 cubic angstroms.

13. The anti-inflammatory composition of any one of embodiments 1 to 12, wherein the striapathic region is characterized by a ratio of the sum of the volume of hydrophobic amino acid residues to the sum of the volume of hydrophilic amino acid residues, wherein the ratio is at least 0.75 or higher.

14. The anti-inflammatory composition of embodiment 9, wherein the striapathic region of the peptide comprises at least one proline residue and adopts an amphipathic conformation that includes a proline-rich helix.

15. The anti-inflammatory composition of embodiment 9, wherein the striapathic region of the peptide adopts an amphipathic beta-strand conformation.

16. The anti-inflammatory composition of any one of embodiments 1 to 13, wherein the striapathic region includes a sequence selected from the group of sequences defined by Formula I: Y1a-Y1b-Y1c-X1a-Y2a-Y2b-Y2c (Formula I).

17. The anti-inflammatory composition of embodiment 16, wherein the module Y1a-Y1b-Y1c has a sequence selected from the group consisting of Phe-Phe-Phe (FFF), Trp-Trp-Trp (WWW), Tyr-Tyr-Tyr (YYY), Leu-Leu-Leu (LLL), Cys-Cys-Cys (CCC), Met-Met-Met (MMM), Val-Val-Val (VVV), and Ile-Ile-Ile (III).

18. The anti-inflammatory composition of embodiment 16, wherein the module Y1a-Y1b-Y1c has a sequence selected from the group consisting of Phe-Phe-Phe (FFF), Trp-Trp-Trp (WWW), and Tyr-Tyr-Tyr (YYY).

19. The anti-inflammatory composition of any one of embodiments 16 to 18, wherein the module Y2a-Y2b-Y2c has a sequence selected from the group consisting of Phe-Phe-Phe (FFF), Trp-Trp-Trp (WWW), Tyr-Tyr-Tyr (YYY), Leu-Leu-Leu (LLL), Cys-Cys-Cys (CCC), Met-Met-Met (MMM), Val-Val-Val (VVV), and Ile-Ile-Ile (III).

20. The anti-inflammatory composition of any one of embodiments 16 to 18, wherein the module Y2a-Y2b-Y2c has a sequence selected from the group consisting of Phe-Phe-Phe (FFF), Trp-Trp-Trp (WWW), and Tyr-Tyr-Tyr (YYY).

21. The anti-inflammatory composition of embodiment 16, wherein the striapathic region includes a sequence selected from the group consisting of FFF-X1a-FFF (SEQ ID NO: 1), WWW-X1a-WWW (SEQ ID NO: 2), and YYY-X1a-YYY (SEQ ID NO: 3).

22. The anti-inflammatory composition of embodiment 16, wherein the sequence of the three modules is selected from the group consisting of LLL-X1a-LLL (SEQ ID NO: 4), CCC-X1a-CCC (SEQ ID NO: 5), MMM-X1a-MMM (SEQ ID NO: 6), VVV-X1a-VVV (SEQ ID NO: 7), and III-X1a-III (SEQ ID NO: 8).

23. The anti-inflammatory composition of any one of embodiments 16 to 22, wherein X1a is selected from the group consisting of Arg (R), His (H), and Lys (K).

24. The anti-inflammatory composition of any one of embodiments 16 to 22, wherein X1a is selected from the group consisting of Glu (E), Gln (Q), Asn (N), and Asp (D).

25. The anti-inflammatory composition of any one of embodiments 16 to 24, wherein the striapathic region includes a sequence selected from the group of sequences defined by Formula II or the group of sequences defined by Formula III: Y1a-Y1b-Y1c-X1a-Y2a-Y2b-Y2c-X2a-Y3a-X3a (Formula II); X2a-Y3a-X3a-Y1a-Y1b-Y1c-X1a-Y2b-Y2c (Formula III).

26. The anti-inflammatory composition of embodiment 25, wherein X2a and X3a are each individually selected from the group consisting of Arg (R), His (H), Lys (K), Glu (E), Gln (Q), Asn (N), and Asp (D).

27. The anti-inflammatory composition of embodiment 25, wherein X2a and X3a are each individually selected from the group consisting of Glu (E), Gln (Q), Asn (N), and Asp (D).

28. The anti-inflammatory composition of any one of embodiments 25 to 27, wherein Y3a is selected from the group consisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val (V), and ne (I).

29. The anti-inflammatory composition of any one of embodiments 25 to 27, wherein Y3a is selected from the group consisting of Phe (F), Trp (W), Tyr (Y), and Leu (L).

30. The anti-inflammatory composition of embodiment 25, wherein the sequence of X2a-Y3a-X3a is selected from the group consisting of EFQ, EFE, EFN, EFD, NFQ, NFE, NFN, NFD, QFQ, QFE, QFN, QFD, DFQ, DFE, DFN, DFD, EWQ, EWE, EWN, EWD, NWQ, NWE, NWN, NWD, QWQ, QWE, QWN, QWD, DWQ, DWE, DWN, DWD, EYQ, EYE, EFN, EYD, NYQ, NYE, NYN, NYD, QYQ, QYE, QYN, QYD, DYQ, DYE, DYN, DYD, ELQ, ELE, ELN, ELD, NLQ, NLE, NLN, NLD, QLQ, QLE, QLN, QLD, DLQ, DLE, DLN, DLD, RFR, RFQ, RFE, RFN, RFD, RWR, RWQ, RWE, RWN, and RWD.

31. The anti-inflammatory composition of embodiment 25, wherein the striapathic region comprises, consists essentially of, or consists of a sequence selected from the group consisting of RP394, RP108-RP123, RP125-131, RP133, RP135-RP141, RP143-RP146, RP148-RP150, RP152-RP165, RP179, RP395, RP211, RP230, RP232, RP258, RP267, RP268, RP271, and RP273.

32. The anti-inflammatory composition of embodiment 25, wherein the striapathic region comprises, consists essentially of, or consists of a sequence selected from the group consisting of RP113 (SEQ ID NO: 39), RP118 (SEQ ID NO: 44), and RP394 (SEQ ID NO: 33).

33. The anti-inflammatory composition of any one of embodiments 1 to 13, wherein the striapathic region includes a sequence selected from the group of sequences defined by Formula VII: Y1a-X1a-X1b-Y2a-Y2b-X2a-X2b-Y3a (Formula VII).

34. The anti-inflammatory composition of embodiment 33, wherein Y2a is selected from the group consisting of Phe (F), Trp (W), and Tyr (Y).

35. The anti-inflammatory composition of embodiment 33, wherein Y2a is selected from the group consisting of Leu (L), Cys (C), Met (M), Val (V), Ile (I), and Ala (A).

36. The anti-inflammatory composition of any one of embodiments 33 to 35, wherein Y2b is selected from the group consisting of Phe (F), Trp (W), and Tyr (Y).

37. The anti-inflammatory composition of any one of embodiments 33 to 35, wherein Y2b is selected from the group consisting of Leu (L), Cys (C), Met (M), Val (V), Ile (I), and Ala (A).

38. The anti-inflammatory composition of any one of embodiments 33 to 37, wherein X1b is selected from the group consisting of Arg (R), Lys (K), and His (H).

39. The anti-inflammatory composition of any one of embodiments 33 to 37, wherein X1b is selected from the group consisting of Asn (N), Gln (Q), Asp (D), and Glu (E).

40. The anti-inflammatory composition of any one of embodiments 33 to 39, wherein X2a is selected from the group consisting of Arg (R), Lys (K), and His (H).

41. The anti-inflammatory composition of any one of embodiments 33 to 39, wherein X2a is selected from the group consisting of Asn (N), Gln (Q), Asp (D), and Glu (E).

42. The anti-inflammatory composition of embodiment 33, wherein the sequence X1b-Y2a-Y2b-X2a is selected from the group consisting of Lys-Phe-Phe-Lys (KFFK; SEQ ID NO: 386), Lys-Trp-Trp-Lys (KWWK; SEQ ID NO: 387), Lys-Tyr-Try-Lys (KYYK; SEQ ID NO: 388), Lys-Phe-Trp-Lys (KFWK; SEQ ID NO: 389), Lys-Trp-Phe-Lys (KWFK; SEQ ID NO: 390), Lys-Phe-Tyr-Lys (KFYK; SEQ ID NO: 391), Lys-Tyr-Phe-Lys (KYFK; SEQ ID NO: 392), Lys-Trp-Tyr-Lys (KWYK; SEQ ID NO: 393), and Lys-Tyr-Trp-Lys (KYWK; SEQ ID NO: 394).

43. The anti-inflammatory composition of embodiment 33, wherein the sequence X1b-Y2a-Y2b-X2a is selected from the group consisting of Arg-Phe-Phe-Arg (RFFR; SEQ ID NO: 395), Arg-Trp-Trp-Arg (RWWR; SEQ ID NO: 396), Arg-Tyr-Try-Arg (RYYR; SEQ ID NO: 397), Arg-Phe-Trp-Arg (RFWR; SEQ ID NO: 398), Arg-Trp-Phe-Arg (RWFR; SEQ ID NO: 399), Arg-Phe-Tyr-Arg (RFYR; SEQ ID NO: 400), Arg-Tyr-Phe-Arg (RYFR; SEQ ID NO: 401), Arg-Trp-Tyr-Arg (RWYR; SEQ ID NO: 402), and Arg-Tyr-Trp-Arg (RYWR; SEQ ID NO: 403).

44. The anti-inflammatory composition of embodiment 33, wherein the sequence X1b-Y2a-Y2b-X2a is selected from the group consisting of His-Phe-Phe-His (HFFH; SEQ ID NO: 404), His-Trp-Trp-His (HWWH; SEQ ID NO: 405), His-Tyr-Try-His (HYYH; SEQ ID NO: 406), His-Phe-Trp-His (HFWH; SEQ ID NO: 407), His-Trp-Phe-His (HWFH; SEQ ID NO: 408), His-Phe-Tyr-His (HFYH; SEQ ID NO: 409), His-Tyr-Phe-His (HYFH; SEQ ID NO: 410). His-Trp-Tyr-His (HWYH; SEQ ID NO: 411), and His-Tyr-Trp-His (HYWH; SEQ ID NO: 132).

45. The anti-inflammatory composition of any one of embodiments 33 to 44, wherein X1a is selected from the group consisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), and Glu (E).

46. The anti-inflammatory composition of any one of embodiments 33 to 44, wherein X1a is selected from the group consisting of Arg (R) and Gln (Q).

47. The anti-inflammatory composition of any one of embodiments 33 to 46, wherein X2b is selected from the group consisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), and Glu (E).

48. The anti-inflammatory composition of any one of embodiments 33 to 46, wherein X2b is selected from the group consisting of Arg (R) and Gln (Q).

49. The anti-inflammatory composition of any one of embodiments 33 to 48, wherein Y1a is selected from the group consisting of Phe (F), Trp (W), and Tyr (Y).

50. The anti-inflammatory composition of any one of embodiments 33 to 48, wherein Y1a is selected from the group consisting of Leu (L), Cys (C), Met (M), Val (V), Ile (I), and Ala (A).

51. The anti-inflammatory composition of any one of embodiments 33 to 50, wherein Y3a is selected from the group consisting of Phe (F), Trp (W), and Tyr (Y).

52. The anti-inflammatory composition of any one of embodiments 33 to 50, wherein Y3a is selected from the group consisting of Leu (L), Cys (C), Met (M), Val (V), Ile (I), and Ala (A).

53. The anti-inflammatory composition of embodiment 33, wherein the striapathic region includes a sequence selected from the group consisting of F-X1a-X1b-FF-X2a-X2b-F (SEQ ID NO: 9), F-X1a-X1b-FF-X2a-X2b-W (SEQ ID NO: 10), W-X1a-X1b-FF-X2a-X2b-F (SEQ ID NO: 11), F-X1a-X1b-FW-X2a-X2b-F (SEQ ID NO: 12), F-X1a-X1b-WF-X2a-X2b-F (SEQ ID NO: 13), F-X1a-X1b-WW-X2a-X2b-F (SEQ ID NO: 14), W-X1a-X1b-WW-X2a-X2b-F (SEQ ID NO: 15), F-X1a-X1b-WW-X2a-X2b-W (SEQ ID NO: 16), W-X1a-X1b-WW-X2a-X2b-W (SEQ ID NO: 17), F-X1a-X1b-FF-X2a-X2b-Y (SEQ ID NO: 18), Y-X1a-X1b-FF-X2a-X2b-F (SEQ ID NO: 19), F-X1a-X1b-FY-X2a-X2b-F (SEQ ID NO: 20), F-X1a-X1b-YF-X2a-X2b-F (SEQ ID NO: 21), F-X1a-X1b-YY-X2a-X2b-F (SEQ ID NO: 22), Y-X1a-X1b-YY-X2a-X2b-F (SEQ ID NO: 23), F-X1a-X1b-YY-X2a-X2b-Y (SEQ ID NO: 24), and Y-X1a-X1b-YY-X2a-X2b-Y (SEQ ID NO: 25), Y-X1a-X1b-YY-X2a-X2b-W (SEQ ID NO: 26), W-X1a-X1b-YY-X2a-X2b-Y (SEQ ID NO: 27), Y-X1a-X1b-YW-X2a-X2b-Y (SEQ ID NO: 28), Y-X1a-X1b-WY-X2a-X2b-Y (SEQ ID NO: 29), Y-X1a-X1b-WW-X2a-X2b-Y (SEQ ID NO: 30), W-X1a-X1b-WW-X2a-X2b-X-Y (SEQ ID NO: 31), and Y-X1a-X1b-WW-X2a-X2b-W (SEQ ID NO: 32).

54. The anti-inflammatory composition of embodiment 53, wherein X1a, X1b, X2a, and X2b are each independently selected from the group consisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), and Glu (E).

55. The anti-inflammatory composition of embodiment 53 or 54, wherein X1b and X2a are each independently selected from the group consisting of Arg (R), Lys (K), and His (H).

56. The anti-inflammatory composition of any one of embodiments 33 to 55, wherein the striapathic region includes a first additional amino acid residue directly bound to Y1a of Formula VII, wherein the first additional amino acid residue is a hydrophobic amino acid residue.

57. The anti-inflammatory composition of embodiment 56, wherein the first additional amino acid residue is selected from the group consisting of Phe (F), Trp (W), and Tyr (Y).

58. The anti-inflammatory composition of any one of embodiments 33 to 55, wherein the striapathic region includes a first additional amino acid residue directly bound to Y3a of Formula VII, wherein the first additional amino acid residue is a hydrophobic amino acid residue.

59. The anti-inflammatory composition of embodiment 58, wherein the first additional amino acid residue is selected from the group consisting of Phe (F), Trp (W), and Tyr (Y).

60. The anti-inflammatory composition of any one of embodiments 33 to 55, wherein the striapathic region includes a first additional amino acid residue directly bound to Y1aof Formula VII, wherein the first additional amino acid residue is a hydrophilic amino acid residue.

61. The anti-inflammatory composition of embodiment 60, wherein the first additional amino acid residue is selected from the group consisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), and Glu (E).

62. The anti-inflammatory composition of any one of embodiments 33 to 55, wherein the striapathic region includes a first additional amino acid residue directly bound to Y3a of Formula VII, wherein the first additional amino acid residue is a hydrophilic amino acid residue.

63. The anti-inflammatory composition of embodiment 62, wherein the first additional amino acid residue is selected from the group consisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), and Glu (E).

64. The anti-inflammatory composition of 56, 57, 60, or 61, wherein the striapathic region includes a second additional amino acid residue directly bound to Y3a of Formula VII, wherein the second additional amino acid residue is a hydrophobic amino acid residue.

65. The anti-inflammatory composition of embodiment 64, wherein the second additional amino acid residue is selected from the group consisting of Phe (F), Trp (W), and Tyr (Y).

66. The anti-inflammatory composition of 58, 59, 62, or 63, wherein the striapathic region includes a second additional amino acid residue directly bound to Y1a of Formula VII, wherein the second additional amino acid residue is a hydrophilic amino acid residue.

67. The anti-inflammatory composition of embodiment 66, wherein the second additional amino acid residue is selected from the group consisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), and Glu (E).

68. The anti-inflammatory composition of embodiment 33, wherein the striapathic region comprises, consists essentially of, or consists of a sequence selected from the group consisting of RP124, RP132, RP134, RP142, RP147, RP151, RP166-RP172, RP175, RP177, RP182, RP183, RP185, RP186, RP424, RP190, RP194, RP198, RP199-RP202, RP204, RP206, RP207, RP209, RP210, RP212-RP216, RP218, RP219, RP425, RP225, RP227, RP233-RP239. RP398, RP241-RP247, RP250-RP256, and RP426.

69. The anti-inflammatory composition of embodiment 33, wherein the striapathic region comprises, consists essentially of, or consists of a sequence selected from the group consisting of RP124 (SEQ ID NO: 106), RP166 (SEQ ID NO: 112), RP182 (SEQ ID NO: 121), and RP183 (SEQ ID NO: 122).

70. The anti-inflammatory composition of any one of embodiments 1 to 15, wherein the striapathic region includes a sequence selected from the group of sequences defined by any one of Formulas I-XLVIII and L:Y1a-Y1b-Y1c-X1aY2a-Y2b-Y2c (Formula I); Y1a-Y1b-Y1c-X1a-Y2a-Y2b-Y2c-X2a-Y3a-X3a (Formula II); X2a-Y3a-X3a-Y1a-Y1b-Y1c-X1a-Y2a-Y2b-Y2c (Formula III); X1a-X1b-X1c-Y2a-X2a-X2b-X2c (Formula IV); Y1a-X1a-X1b-X1c-Y2a-X2b-X2c-Y3a-X3a (Formula V); X1a-X1b-Y2a-Y2b-X2a-X2b (Formula VI); Y1a-X1a-X1b-Y2a-Y2b-X2a-X2b-Y3a (Formula VII); Y1a-X1a-X1b-Y2a-Y2b-X2a-X2b-Y3a-Y3b-X3a (Formula VIII); Y1a-Y1b-X1a-X1b-Y2a-Y2b-X2a-X2b-Y3a-Y3b (Formula IX); Y1a-Y1b-X1a-X1b-Y2a-Y2b-X2a-X2b-Y3a-X3a (Formula X); X1a-Y1a-X2a-X2b-Y2a-Y2b-X3a-X3b-Y3a-Y3b (Formula XI); X1a-Y1a-Y1b-X2a-X2b-Y2a-Y1b-X3a-X3b-Y3a (Formula XII); Y1a-X1a-X1b-Y2a-Y2b-X2a-X2b-X2c-Y3a-Y3b (Formula XIII); X1a-X1b-X1c-Y1a-Y1b-X2a-X2b-Y2a-Y2b-Y2c (Formula XIV); Y1a-Y1b-Y1c-X1a-X1b-Y2a-Y2b-X2a-X2b-X2c (Formula XV); Y1a-Y1b-X1a-X1b-X1c-Y2a-Y2b-X2a-X2b-Y3a (Formula XVI); Y1a-Y1b-X1a-X1b-Y2a-Y2b (Formula XVII); X1a-Y1a-Y1b-X2a-X2b-Y2a-Y2b-X3a (Formula XVIII); Y1a-Y1b-X1a-X1b-Y2a-Y2b-X2a-Y3a-Y3b-X3a (Formula XIX); X1a-Y1a-Y1b-X2a-Y2a-Y2b-X3a-X3b-Y3a-Y3b (Formula XX); Y1a-Y1b-X1a-X1b-Y2a-X2a-X2b-Y3a-Y3b (Formula XXI); X1a-Y1a-Y1b-X2a-X2b-X2c-Y2a-X3a-Y3a-Y3b (Formula XXII); Y1a-Y1b-X1a-Y2a-X2a-X2b-X2c-Y3a-Y3b-X3a (Formula XXIII); X1a-X1b-Y1a-X2a-Y2a-X3a-X3b (Formula XXIV); Y1a-Y1b-Y1c-X1a-X1b-Y2a-X2a-Y3a-X3a-X3b (Formula XXV); X1a-X1b-Y1a-X2a-Y2a-X3a-X3b-Y3a-Y3b-Y3c (Formula XXVI); X1a-X1b-X1c-Y1a-Y1b-Y1c (Formula XXVII); X1a-X1b-X1c-X1d-Y1a-Y1b-Y1c-Y1d (Formula XXVIII); Y1a-X1a-X1b-X1c-X1d-Y2a-Y2b-Y2c-Y2d-X2a (Formula XXIX); X1a-X1b-X1c-X1d-X1c-Y1a-Y1b-Y1c-Y1d-Y1e (Formula XXX); Y1a-Y1b-X1a-X1b-X1c-Y2a-Y2b-Y2c-X2a-X2b (Formula XXXI); X1a-Y1a-X2a-Y2a-X3a-X3b-X3c-Y3a-Y3b-Y3c (Formula XXXII); Y1a-Y1b-Y1c-X1a-X1b-X1c (Formula XXXIII); Y1a-Y1b-Y1c-Y1d-X1a-X1b-X1c-X1d (Formula XXXIV); X1a-Y1a-Y1b-Y1c-Y1d-X2a-X2b-X2c-X2d-Y2a (Formula XXXV); Y1a-Y1b-Y1c-Y1d-Y1e-X1a-X1b-X1c-X1d-X1e (Formula XXXVI); X1a-X1b-Y1a-Y1b-Y1c-X2a-X2b-X2c-Y2a-Y2b (Formula XXXVII); Y1a-Y1b-Y1c-X1a-X1a-X1c-Y2a-X2a-Y3a-X3a (Formula XXXVIII); Y1a-X1a-X1b-X1c-X1d-X1c-Y2a (Formula XXXIX); Y1a-X1a-X1b-X1c-X1d-X1e-Y2a-Y2b-Y2c-Y2d (Formula XL); Y1a-Y1b-X1a-X1b-X1c-X1d-X1e-Y2a-Y2b-Y2c (Formula XLI); Y1a-Y1b-Y1c-X1a-X1b-X1c-X1d-X1e-Y2a-Y2b (Formula XLII); Y1a-Y1b-Y1c-Y1e-X1a-X1b-X1c-X1d-X1e-Y2a (Formula XLIII); X1a-Y1a-Y1b-Y1c-Y1d-Y1e-X2a (Formula XLIV); X1a-Y1a-Y1b-Y1c-Y1d-Y1e-X2a-X2b-X2c-X2d (Formula XLV); X1a-X1b-Y1a-Y1b-Y1c-Y1d-Y1e-X2a-X2b-X2c (Formula XLVI); X1a-X1b-X1c-Y1a-Y1b-Y1c-Y1d-Y1e-X2a-X2b (Formula XLVII); X1a-X1b-X1c-X1d-Y1a-Y1b-Y1c-Y1d-Y1e-X2a (Formula XLVIII); and Y1a-Y1b-X1a-Y2a-Y2b-X2a-Y3a-Y3b-X3a-Y4a (Formula L).

71. The anti-inflammatory composition of embodiment 70, wherein Y1a, Y1b, Y1c, Y2a, Y2b, Y2c, Y3a, Y3b, and Y3c are each individually selected from the group consisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val (V), Ile (I), and Ala (A).

72. The anti-inflammatory composition of embodiment 70, wherein Y1a, Y1b, Y1c, Y2a, Y2b, Y2c, Y3a, Y3b, and Y3c are each individually selected from the group consisting of Phe (F), Trp (W), and Tyr (Y).

73. The anti-inflammatory composition of any one of embodiments 70 to 72, wherein X1a, X1b, X1c, X2a, X2b, X2c, X3a, and X3b are each individually selected from the group consisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), and Glu (E).

74. The anti-inflammatory composition of any one of embodiments 70 to 73, wherein X1a, X1b, X1c, X2a, X2b, X2c, X3a, and X3b are each individually selected from the group consisting of Arg (R), Lys (K), His (H), and Gln (Q).

75. The anti-inflammatory composition of any one of embodiments 70 to 74, wherein the striapathic region includes a first additional amino acid residue directly bound to the N-terminal end of any one of Formulas I-XLVIII and L, wherein the first additional amino acid residue is a hydrophobic amino acid residue.

76. The anti-inflammatory composition of embodiment 70, wherein the first additional amino acid residue is selected from the group consisting of Phe (F), Trp (W), and Tyr (Y).

77. The anti-inflammatory composition of any one of embodiments 70 to 74, wherein the striapathic region includes a first additional amino acid residue directly bound to the C-terminal end of any one of Formulas I-XLVIII and L, wherein the first additional amino acid residue is a hydrophobic amino acid residue.

78. The anti-inflammatory composition of embodiment 77, wherein the first additional amino acid residue is selected from the group consisting of Phe (F), Trp (W), and Tyr (Y).

79. The anti-inflammatory composition of any one of embodiments 70 to 74, wherein the striapathic region includes a first additional amino acid residue directly bound to the N-terminal end of any one of Formulas I-XLVIII and L, wherein the first additional amino acid residue is a hydrophilic amino acid residue.

80. The anti-inflammatory composition of embodiment 79, wherein the first additional amino acid residue is selected from the group consisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), and Glu (E).

81. The anti-inflammatory composition of any one of embodiments 70 to 74, wherein the striapathic region includes a first additional amino acid residue directly bound to the C-terminal end of any one of Formulas I-XLVIII and L, wherein the first additional amino acid residue is a hydrophilic amino acid residue.

82. The anti-inflammatory composition of embodiment 81, wherein the first additional amino acid residue is selected from the group consisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), and Glu (E).

83. The anti-inflammatory composition of any one of embodiments 75, 76, 79, or 80, wherein the striapathic region includes a second additional amino acid residue directly bound to the C-terminal end of any one of Formulas I-XLVIII and L, wherein the second additional amino acid residue is a hydrophobic amino acid residue.

84. The anti-inflammatory composition of embodiment 83, wherein the second additional amino acid residue is selected from the group consisting of Phe (F), Trp (W), and Tyr (Y).

85. The anti-inflammatory composition of any one of embodiments 77, 78, 81, or 82, wherein the striapathic region includes a second additional amino acid residue directly bound to the N-terminal end of any one of Formulas I-XLVIII and L, wherein the second additional amino acid residue is a hydrophilic amino acid residue.

86. The anti-inflammatory composition of embodiment 81, wherein the second additional amino acid residue is selected from the group consisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), and Glu (E).

87. The anti-inflammatory composition of embodiment 70, wherein the striapathic region comprises, consists essentially of, or consists of a sequence selected from the group consisting of RP396, RP405, RP174, RP176, RP178, RP180-181, RP184, RP408, RP187, RP416, RP188, RP189, RP388, RP417, RP191-RP193, RP404, RP196, RP397, RP197, RP402, RP203, RP409, RP205, RP208, RP217, RP220-RP224, RP226, RP229, RP231, RP240, RP248, RP249, RP415, RP257, RP259-RP266, RP269, RP272, RP406, RP422, RP407, RP400, RP419, RP401, RP423, RP411, RP418, RP428, RP420, RP421, RP429, RP413, RP430, RP270.

88. The anti-inflammatory composition of any one of embodiments 1 to 9 or 15, wherein the striapathic region includes a sequence selected from the group of sequences defined by Formula XLIX:

Y1a-X1a-Y2a-X2a-Y3a-X3a  (Formula XLIX).

89. The anti-inflammatory composition of embodiment 88, wherein Y1a, Y2a, and Y3a are each independently selected from the group consisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Ile (I), Cys (C), and Met (M).

90. The anti-inflammatory composition of embodiment 88, wherein Y1a, Y2a, and Y3a are each independently selected from the group consisting of Phe (F), Trp (W), and Tyr (Y).

91. The anti-inflammatory composition of any one of embodiments 88 to 90, wherein X1a, X2a, and X3a are each independently selected from the group consisting of Arg (R), Lys (K), His (H), Gln (Q), Glu (E), Asn (N), and Asp (D).

92. The anti-inflammatory composition of any one of embodiments 88 to 90, wherein X1a, X2a, and X3a are each independently selected from the group consisting of Arg (R), Lys (K), and His (H).

93. The anti-inflammatory composition of any one of embodiments 88 to 92, wherein the striapathic region includes a first additional amino acid residue directly bound to Y1a of Formula XLIX, wherein the first additional amino acid residue is a hydrophilic amino acid residue.

94. The anti-inflammatory composition of embodiment 93, wherein the first additional amino acid residue is selected from the group consisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), and Glu (E).

95. The anti-inflammatory composition of embodiment 93, wherein the first additional amino acid residue is selected from the group consisting of Arg (R), Lys (K), and His (H).

96. The anti-inflammatory composition of any one of embodiments 88 to 92, wherein the striapathic region includes a first additional amino acid residue directly bound to X3a of Formula XLIX, wherein the first additional amino acid residue is a hydrophobic amino acid residue.

97. The anti-inflammatory composition of embodiment 96, wherein the first additional amino acid residue is selected from the group consisting of Phe (F), Trp (W), (Tyr), Leu (L), Ile (I), Cys (C), and Met (M).

98. The anti-inflammatory composition of embodiment 96, wherein the first additional amino acid residue is selected from the group consisting of Phe (F), Trp (W), and (Tyr).

99. The anti-inflammatory composition of any one of embodiments 93 to 95, wherein the striapathic region includes a second additional amino acid residue directly bound to X3a of Formula XLIX, wherein the second additional amino acid residue is a hydrophobic amino acid residue.

100. The anti-inflammatory composition of embodiment 99, wherein the second additional amino acid residue is selected from the group consisting of Phe (F), Trp (W), (Tyr), Leu (L), Ile (I), Cys (C), and Met (M).

101. The anti-inflammatory composition of embodiment 99, wherein the second additional amino acid residue is selected from the group consisting of Phe (F), Trp (W), and Tyr (Y).

102. An anti-inflammatory composition comprising a peptide, wherein the peptide is 3 to 24 amino acids residues in length and comprises a striapathic region having at least 70% identity with the sequence NFNFFFRFFF (RP394, SEQ ID NO: 33), wherein the peptide binds to the dimerization site on a NFkB Class II protein.

103. The anti-inflammatory composition of embodiment 102, wherein the peptide also binds to human serum albumin.

104. The anti-inflammatory composition of embodiment 102 or 103, wherein the differences between the striapathic region of the peptide and the sequence NFNFFFRFFF (SEQ ID NO: 33) are limited to conservative or highly conservative amino acid substitutions.

105. The anti-inflammatory composition of embodiment 102 or 103, wherein the striapathic region of the peptide differs from the sequence NFNFFFRFFF (SEQ ID NO: 33) by substitution of one or more of the phenylalanine (F) residues with an amino acid residue selected from the group consisting of Trp (W), Tyr (Y), His (H), and Leu (L).

106. The anti-inflammatory composition of embodiment 102 or 103, wherein the striapathic region of the peptide differs from the sequence NFNFFFRFFF (SEQ ID NO: 33) by the deletion of one, two, or three amino acids.

107. The anti-inflammatory composition of embodiment 106, wherein the deleted amino acids are located at the N-terminal end, the C-terminal end, or both ends of the sequence NFNFFFRFFF (SEQ ID NO: 33).

108. An anti-inflammatory composition comprising a peptide, wherein the peptide is 3 to 24 amino acids residues in length and comprises a striapathic region having at least 70% identity with the sequence FFFRFFFNFN (RP118, SEQ ID NO: 44), wherein the peptide binds to the dimerization site on a NFkB Class II protein.

109. The anti-inflammatory composition of embodiment 108, wherein the peptide also binds to human serum albumin.

110. The anti-inflammatory composition of embodiment 108 or 109, wherein the differences between the striapathic region of the peptide and the sequence FFFRFFFNFN (SEQ ID NO: 44) are limited to conservative or highly conservative amino acid substitutions.

111. The anti-inflammatory composition of embodiment 108 or 109, wherein the striapathic region of the peptide differs from the sequence FFFRFFFNFN (SEQ ID NO: 44) by substitution of one or more of the phenylalanine (F) residues with an amino acid residue selected from the group consisting of Trp (W), Tyr (Y), His (H), and Leu (L).

112. The anti-inflammatory composition of embodiment 108 or 109, wherein the striapathic region of the peptide differs from the sequence FFFRFFFNFN (SEQ ID NO: 44) by the deletion of one, two, or three amino acids.

113. The anti-inflammatory composition of embodiment 112, wherein the deleted amino acids are located at the N-terminal end, the C-terminal end, or both ends of the sequence FFFRFFFNFN (SEQ ID NO: 44).

114. An anti-inflammatory composition comprising a peptide, wherein the peptide is 3 to 24 amino acids residues in length and comprises a striapathic region having at least 70% identity with the sequence FFRKFAKRFK (RP183, SEQ ID NO: 122), wherein the peptide binds to the dimerization site on a NFkB Class II protein.

115. The anti-inflammatory composition of embodiment 114, wherein the peptide also binds to human serum albumin.

116. The anti-inflammatory composition of embodiment 114 or 115, wherein the differences between the striapathic region of the peptide and the sequence FFRKFAKRFK (SEQ ID NO: 122) are limited to conservative or highly conservative amino acid substitutions.

117. The anti-inflammatory composition of embodiment 114 or 115, wherein the striapathic region of the peptide differs from the sequence FFRKFAKRFK (SEQ ID NO: 122) by substitution of one or more of the phenylalanine (F) residues with an amino acid residue selected from the group consisting of Trp (W), Tyr (Y), and Leu (L).

118. The anti-inflammatory composition of embodiment 114 or 115, wherein the striapathic region of the peptide differs from the sequence FFRKFAKRFK (SEQ ID NO: 122) by the deletion of one, two, or three amino acids.

119. The anti-inflammatory composition of embodiment 118, wherein the deleted amino acids are located at the N-terminal end, the C-terminal end, or both ends of the sequence FFRKFAKRFK (SEQ ID NO: 122).

120. An anti-inflammatory composition comprising a peptide, wherein the peptide is 3 to 24 amino acids residues in length and comprises a striapathic region having at least 70% identity with the sequence KFRKAFKRFF (RP182, SEQ ID NO: 121), wherein the peptide binds to the dimerization site on a NFkB Class II protein.

121. The anti-inflammatory composition of embodiment 120, wherein the peptide also binds to human serum albumin.

122. The anti-inflammatory composition of embodiment 120 or 121, wherein the differences between the striapathic region of the peptide and the sequence KFRKAFKRFF (SEQ ID NO: 121) are limited to conservative or highly conservative amino acid substitutions.

123. The anti-inflammatory composition of embodiment 120 or 121, wherein the striapathic region of the peptide differs from the sequence KFRKAFKRFF (SEQ ID NO: 121) by substitution of one or more of the phenylalanine (F) residues with an amino acid residue selected from the group consisting of Trp (W), Tyr (Y), and Leu (L).

124. The anti-inflammatory composition of embodiment 120 or 121, wherein the striapathic region of the peptide differs from the sequence KFRKAFKRFF (SEQ ID NO: 121) by the deletion of one, two, or three amino acids.

125. The anti-inflammatory composition of embodiment 124, wherein the deleted amino acids are located at the N-terminal end, the C-terminal end, or both ends of the sequence KFRKAFKRFF (SEQ ID NO: 121).

126. The anti-inflammatory composition of any one of embodiments 1 to 125, wherein the peptide binds to the dimerization site on Rel B (SEQ ID NO: 367) with a binding energy of at least −650 kcal/mol.

127. The anti-inflammatory composition of any one of embodiments 1 to 126, wherein the peptide binds to the dimerization site on Rel B (SEQ ID NO: 367) and directly contacts at least one amino acid residue of Rel B selected from the group consisting of Glu 298, Tyr-300, Leu-301, Leu-302, Asp-330, His-332, and Leu-371.

128. The anti-inflammatory composition of embodiment 127, wherein the peptide, when bound to the dimerization site on Rel B, forms an ionic bond with Asp-330, forms an ionic bond with His-332, and/or makes a hydrophobic contact with Leu-371.

129. The anti-inflammatory composition of any one of embodiments 1 to 128, wherein the peptide binds to at least one signaling molecule selected from the group consisting of TGFβ (SEQ ID NO: 368), Notch1 (SEQ ID NO: 369), Wnt8R (SEQ ID NO: 370), TRAIL (SEQ ID NO: 371), IL6R (SEQ ID NO: 372), IL10R (SEQ ID NO: 373), EGFR (SEQ ID NO: 374), CDK6 (SEQ ID NO: 375), Histone Methyl Transferase (HMT) (SEQ ID NO: 376), CD47 (SEQ ID NO: 377), SIRP-α (SEQ ID NO: 378), CD206 (SEQ ID NO: 379), TGM2 (SEQ ID NO: 380); LEGUMAIN (SEQ ID NO: 137), CD209 (SEQ ID NO: 140), FAS (SEQ ID NO: 152), PD-1 (SEQ ID NO: 159), MKK7 (SEQ ID NO: 166), and RNR (SEQ ID NO: 168).

130. The anti-inflammatory composition of embodiment 129, wherein the peptide binds to TGFβ (SEQ ID NO: 368) with a binding energy of at least −650 kcal/mol.

131. The anti-inflammatory composition of embodiment 129 or 130, wherein the peptide binds to TGFβ (SEQ ID NO: 368) and directly contacts at least one amino acid residue of TGFβ selected from the group consisting of Leu-20, Ile-22, Phe-24, Asp-27, Leu-28, Trp-30, Trp-32, Tyr-39, Phe-43, Pro-80, Leu-83, Leu-101, and Ser-112.

132. The anti-inflammatory composition of any one of embodiments 129 to 131, wherein the peptide binds to Notch1 (SEQ ID NO: 369) with a binding energy of at least −650 kcal/mol.

133. The anti-inflammatory composition of any one of embodiments 120 to 123, wherein the peptide binds to Notch (SEQ ID NO: 369) and directly contacts at least one amino acid residue of Notch selected from the group consisting of Phe-1520, Gln-1523, Arg-1524, Glu-1526, Ala-1553, Glu-1556, Trp-1557, Cys-1562, His-1602, Arg-1684, Gln-1685, Cys-1686, Ser-1691, Cys-1693, Phe-1694, and Phe-1703.

134. The anti-inflammatory composition of any one of embodiments 129 to 133, wherein the peptide binds to Wnt8R (SEQ ID NO: 370) with a binding energy of at least −600 kcal/mol.

135. The anti-inflammatory composition of any one of embodiments 129 to 134, wherein the peptide binds to Wnt8R (SEQ ID NO: 370) and directly contacts at least one amino acid residue of Wnt8R selected from the group consisting of Tyr-52, Gln-56, Phe-57, Asn-58, Met-91, Tyr-100, Lys-101, Pro-103, Pro-105, Pro-106, Arg-137, and Asp-145.

136. The anti-inflammatory composition of any one of embodiments 129 to 135, wherein the peptide binds to TRAIL (SEQ ID NO: 371) with a binding energy of at least −650 kcal/mol.

137. The anti-inflammatory composition of any one of embodiments 120 to 127, wherein the peptide binds to TRAIL (SEQ ID NO: 371) and directly contacts at least one amino acid residue of TRAIL selected from the group consisting of Arg-130, Arg-158, Ser-159, Gly-160, His-161, Phe-163. Tyr-189, Arg-189, Gln-193, Glu-195, Glu-236, Tyr-237, Leu-239, Asp-267, Asp-269, His-270, and Glu-271.

138. The anti-inflammatory composition of any one of embodiments 129 to 137, wherein the peptide binds to IL6R (SEQ ID NO: 372) with a binding energy of at least −600 kcal/mol.

139. The anti-inflammatory composition of any one of embodiments 129 to 138, wherein the peptide binds to IL6R (SEQ ID NO: 372) and directly contacts at least one amino acid residue of IL6R selected from the group consisting of Glu-163, Gly-164, Phe-168, Gln-190, Phe-229, Tyr-230, Phe-279, and Gln-281.

140. The anti-inflammatory composition of any one of embodiments 129 to 139, wherein the peptide binds to IL10R (SEQ ID NO: 373) with a binding energy of at least −600 kcal/mol.

141. The anti-inflammatory composition of any one of embodiments 129 to 140, wherein the peptide binds to IL10R (SEQ ID NO: 373) and directly contacts at least one amino acid residue of IL10R selected from the group consisting of Tyr-43, Ile-45, Glu-46, Asp-61, Asn-73, Arg-76, Asn-94, Arg-96, Phe-143, Ala-189, Ser-190, and Ser-191.

142. The anti-inflammatory composition of any one of embodiments 129 to 141, wherein the peptide binds to EGFR (SEQ ID NO: 374) with a binding energy of at least −650 kcal/mol.

143. The anti-inflammatory composition of any one of embodiments 129 to 142, wherein the peptide binds to EGFR (SEQ ID NO: 374) and directly contacts at least one amino acid residue of EGFR selected from the group consisting of Leu-10, Thr-40, Trp-41, Leu-63, His-66, Asp-68, Leu-88, Tyr-101, Asp-48, and Phe-51.

144. The anti-inflammatory composition of any one of embodiments 129 to 143, wherein the peptide binds to CDK6 (SEQ ID NO: 375) with a binding energy of at least −600 kcal/mol.

145. The anti-inflammatory composition of any one of embodiments 129 to 144, wherein the peptide binds to CDK6 (SEQ ID NO: 375) and directly contacts at least one amino acid residue of CDK6 selected from the group consisting of Val-142, Arg-144, Asp-145, Ser-171, Val-180, Val-181, Leu-183, Arg-186, Val-190, Gln-193, Tyr-196, and Val-200.

146. The anti-inflammatory composition of any one of embodiments 129 to 145, wherein the peptide binds to histone methyl transferase (HMT) (SEQ ID NO: 376) with a binding energy of at least −600 kcal/mol.

147. The anti-inflammatory composition of any one of embodiments 129 to 146, wherein the peptide binds to HMT (SEQ ID NO: 376) and directly contacts at least one amino acid residue of HMT selected from the group consisting of Asn-69, His-70, Ser-71, Lys-72, Asp-73, Pro-74, and Asn-75.

148. The anti-inflammatory composition of any one of embodiments 129 to 147, wherein the peptide binds to the SIRP-α binding site on CD47 (SEQ ID NO: 377) with a binding energy of at least −550 kcal/mol.

149. The anti-inflammatory composition of any one of embodiments 129 to 148, wherein the peptide binds to CD47 (SEQ ID NO: 377) and directly contacts at least one amino acid residue of CD47 selected from the group consisting of Glu-29, Ala-30, Glu-35, Val-36, Tyr-37, Lys-39, Thr-49, Asp-51, Glu-97, Thr-99, Leu-101, Thr-102, Arp-103, Glu-104, and Glu-106.

150. The anti-inflammatory composition of any one of embodiments 129 to 149, wherein the peptide binds to the CD47 binding site on SIRP-α (SEQ ID NO: 378) with a binding energy of at least −600 kcal/mol.

151. The anti-inflammatory composition of any one of embodiments 129 to 150, wherein the peptide binds to SIRP-α (SEQ ID NO: 378) and directly contacts at least one amino acid residue of SIRP-α selected from the group consisting of Leu-30, Gln-37, Gln-52, Lys-53, Ser-66, Thr-67, Arg-69, Met-72, Phe-74, Lys-96, and Asp-100.

152. The anti-inflammatory composition of any one of embodiments 129 to 151, wherein the peptide binds to CD206 (SEQ ID NO: 379) with a binding energy of at least −650 kcal/mol.

153. The anti-inflammatory composition of any one of embodiments 129 to 152, wherein the peptide binds to CD206 (SEQ ID NO: 379) and directly contacts at least one amino acid residue of CD206 selected from the group consisting of Glu-725, Tyr-729, Glu-733, Asn-747, and Asp-748.

154. The anti-inflammatory composition of any one of embodiments 129 to 153, wherein the peptide binds to TGM2 (SEQ ID NO: 380) with a binding energy of at least −650 kcal/mol.

155. The anti-inflammatory composition of any one of embodiments 129 to 154, wherein the peptide binds to TGM2 (SEQ ID NO: 380) and directly contacts at least one amino acid residue of TGM2 selected from the group consisting of Cys-277, His-335, and Asp-358.

156. The anti-inflammatory composition of any one of embodiments 129 to 155, wherein the peptide binds to LEGUMAIN (SEQ ID NO: 137) with a binding energy of at least −600 kcal/mol.

157. The anti-inflammatory composition of any one of embodiments 129 to 156, wherein the peptide binds to LEGUMAIN (SEQ ID NO: 137) and directly contacts at least one amino acid residue of LEGUMAIN selected from the group consisting of Asn-44, Arg-46, His-159, Glu-189, Cys-191, Ser-217, Ser-218 and Asp-233.

158. The anti-inflammatory composition of any one of embodiments 129 to 157, wherein the peptide binds to CD209 (SEQ ID NO: 140) with a binding energy of at least −600 kcal/mol.

159. The anti-inflammatory composition of any one of embodiments 129 to 158, wherein the peptide binds to CD209 (SEQ ID NO: 140) and directly contacts at least one amino acid residue of CD209 selected from the group consisting of Phe-269, Glu-280, Glu-303, Asn-305, Asn-306, Glu-310, Asp-311, Ser-316, Gly-317, Asn-321 and Lys-324.

160. The anti-inflammatory composition of any one of embodiments 129 to 159, wherein the peptide binds to FAS (SEQ ID NO: 152) with a binding energy of at least −600 kcal/mol.

161. The anti-inflammatory composition of any one of embodiments 129 to 160, wherein the peptide binds to FAS (SEQ ID NO: 152) and directly contacts at least one amino acid residue of FAS selected from the group consisting of Lys-251, Lys-296, Lys-299, Leu-303, Leu-306, Ala-307, Glu-308, Lys-309, Gln-311, Ile-314, Leu-315, Asp-317, Ile-318 and Thr-319.

162. The anti-inflammatory composition of any one of embodiments 129 to 161, wherein the peptide binds to PD-1 (SEQ ID NO: 159) with a binding energy of at least −600 kcal/mol.

163. The anti-inflammatory composition of any one of embodiments 129 to 162, wherein the peptide binds to PD-1 (SEQ ID NO: 159) and directly contacts at least one amino acid residue of PD-1 selected from the group consisting of Val-64, Asn-66. Tyr-68, Met-70, Thr-76, Lys-78, Thr-120. Leu-122, Ala-125, and Ser-127.

164. The anti-inflammatory composition of any one of embodiments 129 to 163, wherein the peptide binds to MKK7 (SEQ ID NO: 166) with a binding energy of at least −600 kcal/mol.

165. The anti-inflammatory composition of any one of embodiments 129 to 164, wherein the peptide binds to MKK7 (SEQ ID NO: 166) and directly contacts at least one amino acid residue of MKK7 selected from the group consisting of Met-142, Val-150, Lys-152, Lys-165, Met-212, Met-215, Thr-217, Lys-221, Leu-266, Cys-276 and Asp-277.

166. The anti-inflammatory composition of any one of embodiments 129 to 165, wherein the peptide binds to RNR (SEQ ID NO: 168) with a binding energy of at least −600 kcal/mol.

167. The anti-inflammatory composition of any one of embodiments 129 to 166, wherein the peptide binds to RNR (SEQ ID NO: 168) and directly contacts at least one amino acid residue of RNR selected from the group consisting of Asn-426, Leu-427, Cys-428, Glu-430, Met-606, Pro-608 and Ala-610.

168. The anti-inflammatory composition of any one of embodiments 1 to 167, wherein the peptide binds to human serum albumin (HSA) (SEQ ID NO: 381) with a binding energy of at least −650 kcal/mol.

169. The anti-inflammatory composition of any one of embodiments 1 to 168, wherein the peptide comprises a striapathic region that is composed exclusively of D-form amino acid residues.

170. The anti-inflammatory composition of any one of embodiments 1 to 169, wherein the peptide is in solution at a concentration of about 0.1 mg/ml to about 100 mg/ml.

171. The anti-inflammatory composition of any one of embodiments 1 to 170, wherein the composition contains about 1 mg to about 500 mg of the peptide.

172. The anti-inflammatory composition of embodiment 158 or 171, wherein the composition is substantially free of protein other than the peptide.

173. An anti-inflammatory composition comprising a first peptide as defined in any one of embodiments 1 to 171 in combination with a second peptide as defined in any one of embodiments 1 to 171, wherein the first and second peptides can have the same sequence or different sequences.

174. The anti-inflammatory composition of embodiment 173, wherein the first and second peptides are linked together by a peptide bond, a peptide linker, or a non-peptide linker.

175. The anti-inflammatory composition of embodiment 173, wherein the first and second peptides are linked together by a peptide linker, wherein the peptide linker has a sequence selected from the group consisting of Gly-Gly-Gly (GGG), Gly-Gly-Gly-Arg (GGGR; SEQ ID NO: 412), Gly-Pro-Gly (GPG), and Gly-Pro-Gly-Arg (GPGR; SEQ ID NO: 413).

176. The anti-inflammatory composition of embodiment 174 or 175, wherein the linked first and second peptides bind to the dimerization site on Rel B (SEQ ID NO: 367) with a binding energy of at least −700 kcal/mol.

177. The anti-inflammatory composition of any one of embodiments 1 to 171 and embodiments 173 to 176, further comprising serum albumin.

178. The anti-inflammatory composition of embodiment 177, wherein the composition is substantially free of blood proteins other than serum albumin.

179. A pharmaceutical composition comprising the anti-inflammatory composition of any one of embodiments 1 to 178, and a pharmaceutically acceptable carrier.

180. The pharmaceutical composition of embodiment 179, wherein the composition comprises a chemotherapeutic agent.

181. A method of treating a condition associated with chronic inflammation, the method comprising administering a composition according to any one of embodiments 1 to 180 to a subject suffering from the condition.

182. The method of embodiment 181, wherein the condition is selected from the group consisting of irritable bowel disease, ulcerative colitis, colitis, Crohn's disease, idiopathic pulmonary fibrosis, asthma, keratitis, arthritis, osteoarthritis, rheumatoid arthritis, auto-immune diseases, a feline or human immunodeficiency virus (FIV or HIV) infection, and cancer.

183. The method of embodiment 181 or 182, wherein the subject is a mammal.

184. The method of any one of embodiments 181 to 183, wherein the subject is a human.

185. The method of any one of embodiments 181 to 184, wherein the anti-inflammatory composition is administered in a dosage that includes between about 1 mg and about 500 mg of peptide.

186. The method of any one of embodiments 181 to 185, wherein the anti-inflammatory composition is administered intravenously, intraperitoneally, parenteral, orthotopically, subcutaneously, topically, nasally, by means of an implantable depot, using nanoparticle-based delivery systems, microneedle patch, microspheres, beads, osmotic or mechanical pumps, and/or other mechanical means.

187. The method of any one of embodiments 181 to 186, wherein the anti-inflammatory composition is administered in conjunction with another drug known to be effective in treating the condition.

188. The method of embodiment 187, wherein the anti-inflammatory composition is administered prior to, at the same time as, or after the administration of the other drug.

189. A method of treating fibrosis in a subject, the method comprising administering a composition according to any one of embodiments 1 to 180 to the subject.

190. The method of embodiment 189, wherein the fibrosis is selected from the group consisting of pulmonary fibrosis, dermal fibrosis, hepatic fibrosis, renal fibrosis, and fibrosis caused by ionizing radiation.

191. The method of embodiment 189 or 190, wherein the subject is a mammal.

192. The method of any one of embodiments 189 to 191, wherein the subject is a human.

193. The method of any one of embodiments 189 to 192, wherein the anti-inflammatory composition is administered in a dosage that includes between about 1 mg and about 500 mg of peptide.

194. The method of any one of embodiments 189 to 193, wherein the anti-inflammatory composition is administered intravenously, intraperitoneally, parenteral, orthotopically, subcutaneously, topically, nasally, by means of an implantable depot, using nanoparticle-based delivery systems, microneedle patch, microspheres, beads, osmotic or mechanical pumps, and/or other mechanical means.

195. The method of any one of embodiments 189 to 194, wherein the anti-inflammatory composition is administered in conjunction with another drug known to be effective in treating fibrosis.

196. The method of embodiment 195, wherein the anti-inflammatory composition is administered prior to, at the same time as, or after the administration of the other drug.

197. A method of reducing pro-inflammatory cytokine levels in a subject suffering from a chronic inflammatory condition, the method comprising administering a composition according to any one of embodiments 1 to 180 to the subject.

198. The method of embodiment 197, wherein the chronic inflammatory condition is selected from the group consisting of irritable bowel disease, ulcerative colitis, colitis, Crohn's disease, idiopathic pulmonary fibrosis, asthma, keratitis, arthritis, osteoarthritis, rheumatoid arthritis, auto-immune diseases, a feline or human immunodeficiency virus (FIV or HIV) infection, and cancer.

199. The method of embodiment 197 or 198, wherein the method reduces the level of at least one cytokine selected from group consisting of NF-kB, TNFα, IL1, IL6, IL12, MMP-1, MMP-9, MCP-1, IL8, IL7, and IL23.

200. The method of embodiment 199, wherein the level of the at least one cytokine is reduced by at least 10%.

201. The method of any one of embodiments 197 to 200, wherein the subject is a mammal.

202. The method of any one of embodiments 197 to 201, wherein the subject is a human.

203. The method of any one of embodiments 197 to 202, wherein the anti-inflammatory composition is administered in a dosage that includes between about 1 mg and about 500 mg of peptide.

204. The method of any one of embodiments 197 to 203, wherein the anti-inflammatory composition is administered intravenously, intraperitoneally, parenteral, orthotopically, subcutaneously, topically, nasally, by means of an implantable depot, using nanoparticle-based delivery systems, microneedle patch, microspheres, beads, osmotic or mechanical pumps, and/or other mechanical means.

205. The method of any one of embodiments 197 to 204, wherein the anti-inflammatory composition is administered in conjunction with another drug known to be effective in treating the chronic inflammatory condition that the subject is suffering from.

206. The method of embodiment 205, wherein the anti-inflammatory composition is administered prior to, at the same time as, or after the administration of the other drug.

207. A method of treating cancer in a subject, the method comprising administering an anti-inflammatory composition according to any one of embodiments 1 to 180 to the subject.

208. The method of embodiment 207, wherein the cancer is selected from the group consisting of colon cancer, and breast cancer.

209. The method of embodiment 207 or 208, wherein the anti-inflammatory composition is administered in conjunction with a chemotherapeutic agent or cell therapy.

210. The method of embodiment 209, wherein the chemotherapeutic agent or cell therapy is selected from the group consisting of steroids, anthracyclines, thyroid hormone replacement drugs, thymidylate-targeted drugs, checkpoint inhibitor drugs, Chimeric Antigen Receptor/T cell therapies, and other cell therapies.

211. The method of embodiment 209, wherein the chemotherapeutic agent is selected from the group consisting of Gemcitabine, Docetaxel, Bleomycin, Erlotinib. Gefitinib, Lapatinib. Imatinib, Dasatinib, Nilotinib, Bosutinib, Crizotinib, Ceritinib, Trametinib, Bevacizumab. Sunitinib. Sorafenib, Trastuzumab, Ado-trastuzumab emtansine, Rituximab, Ipilimumab. Rapamycin, Temsirolimus, Everolimus, Methotrexate, Doxorubicin, Abraxane, Folfirinox, Cisplatin, Carboplatin, 5-fluorouracil, Teysumo, Paclitaxel, Prednisone, Levothyroxine, and Pemetrexed.

212. The method of any one of embodiments 209 to 211, wherein the anti-inflammatory composition is administered prior to, at the same time as, or after the administration of the chemotherapeutic agent or cell therapy.

213. The method of embodiment 207 or 208, wherein the anti-inflammatory composition is administered in conjunction with radiation therapy.

214. The method of embodiment 213, wherein the anti-inflammatory composition is administered prior to, or after the administration of the radiation therapy.

215. The method of any one of embodiments 207 to 214, wherein the subject is a mammal.

216. The method of any one of embodiments 207 to 215, wherein the subject is a human.

217. The method of any one of embodiments 207 to 216, wherein the anti-inflammatory composition is administered in a dosage that includes between about 1 mg and about 500 mg of peptide.

218. The method of any one of embodiments 207 to 217, wherein the anti-inflammatory composition is administered intravenously, intraperitoncally, parenteral, orthotopically, subcutaneously, nasally, by means of an implantable depot, using nanoparticle-based delivery systems, microneedle patch, microspheres, beads, osmotic or mechanical pumps, and/or other mechanical means.

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<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (2)..(3)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (6)..(7)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<400> SEQENCE: 16

Phe Xaa Xaa Trp Trp Xaa Xaa Trp

1 5

<210> SEQ ID NO: 17

<211> LENGTH: 8

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (2)..(3)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (6)..(7)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<400> SEQENCE: 17

Trp Xaa Xaa Trp Trp Xaa Xaa Trp

1 5

<210> SEQ ID NO: 18

<211> LENGTH: 8

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (2)..(3)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (6)..(7)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<400> SEQENCE: 18

Phe Xaa Xaa Phe Phe Xaa Xaa Tyr

1 5

<210> SEQ ID NO: 19

<211> LENGTH: 8

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (2)..(3)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (6)..(7)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<400> SEQENCE: 19

Tyr Xaa Xaa Phe Phe Xaa Xaa Phe

1 5

<210> SEQ ID NO: 20

<211> LENGTH: 8

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (2)..(3)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (6)..(7)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<400> SEQENCE: 20

Phe Xaa Xaa Phe Tyr Xaa Xaa Phe

1 5

<210> SEQ ID NO: 21

<211> LENGTH: 8

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (2)..(3)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (6)..(7)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<400> SEQENCE: 21

Phe Xaa Xaa Tyr Phe Xaa Xaa Phe

1 5

<210> SEQ ID NO: 22

<211> LENGTH: 8

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (2)..(3)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (6)..(7)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<400> SEQENCE: 22

Phe Xaa Xaa Tyr Tyr Xaa Xaa Phe

1 5

<210> SEQ ID NO: 23

<211> LENGTH: 8

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (2)..(3)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (6)..(7)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<400> SEQENCE: 23

Tyr Xaa Xaa Tyr Tyr Xaa Xaa Phe

1 5

<210> SEQ ID NO: 24

<211> LENGTH: 8

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (2)..(3)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (6)..(7)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<400> SEQENCE: 24

Phe Xaa Xaa Tyr Tyr Xaa Xaa Tyr

1 5

<210> SEQ ID NO: 25

<211> LENGTH: 8

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (2)..(3)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (6)..(7)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<400> SEQENCE: 25

Tyr Xaa Xaa Tyr Tyr Xaa Xaa Tyr

1 5

<210> SEQ ID NO: 26

<211> LENGTH: 8

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (2)..(3)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (6)..(7)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<400> SEQENCE: 26

Tyr Xaa Xaa Tyr Tyr Xaa Xaa Trp

1 5

<210> SEQ ID NO: 27

<211> LENGTH: 8

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (2)..(3)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (6)..(7)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<400> SEQENCE: 27

Trp Xaa Xaa Tyr Tyr Xaa Xaa Tyr

1 5

<210> SEQ ID NO: 28

<211> LENGTH: 8

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (2)..(3)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (6)..(7)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<400> SEQENCE: 28

Tyr Xaa Xaa Tyr Trp Xaa Xaa Tyr

1 5

<210> SEQ ID NO: 29

<211> LENGTH: 8

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (2)..(3)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (6)..(7)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<400> SEQENCE: 29

Tyr Xaa Xaa Trp Tyr Xaa Xaa Tyr

1 5

<210> SEQ ID NO: 30

<211> LENGTH: 8

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (2)..(3)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (6)..(7)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<400> SEQENCE: 30

Tyr Xaa Xaa Trp Trp Xaa Xaa Tyr

1 5

<210> SEQ ID NO: 31

<211> LENGTH: 8

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (2)..(3)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (6)..(7)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<400> SEQENCE: 31

Trp Xaa Xaa Trp Trp Xaa Xaa Tyr

1 5

<210> SEQ ID NO: 32

<211> LENGTH: 8

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (2)..(3)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (6)..(7)

<223> OTHER INFORMATION: Xaa is selected from Arg (R), His (H), Lys (K),

Glu (E), Gln (Q), Asn (N), and Asp (D)

<400> SEQENCE: 32

Tyr Xaa Xaa Trp Trp Xaa Xaa Trp

1 5

<210> SEQ ID NO: 33

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 33

Asn Phe Asn Phe Phe Phe Arg Phe Phe Phe

1 5 10

<210> SEQ ID NO: 34

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 34

Trp Trp Trp Arg Trp Trp Trp Glu Trp Gln

1 5 10

<210> SEQ ID NO: 35

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 35

Glu Phe Asn Phe Phe Phe Arg Phe Phe Phe

1 5 10

<210> SEQ ID NO: 36

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 36

Asp Phe Glu Phe Phe Phe Arg Phe Phe Phe

1 5 10

<210> SEQ ID NO: 37

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 37

Gln Phe Glu Phe Phe Phe Arg Phe Phe Phe

1 5 10

<210> SEQ ID NO: 38

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 38

Glu Phe Glu Phe Phe Phe Arg Phe Phe Phe

1 5 10

<210> SEQ ID NO: 39

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 39

Phe Phe Phe Arg Phe Phe Phe Glu Phe Gln

1 5 10

<210> SEQ ID NO: 40

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 40

Phe Phe Phe Arg Phe Phe Phe Glu Phe Glu

1 5 10

<210> SEQ ID NO: 41

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 41

Phe Phe Phe Arg Phe Phe Phe Glu Phe Asp

1 5 10

<210> SEQ ID NO: 42

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 42

Phe Phe Phe Arg Phe Phe Phe Asn Phe Glu

1 5 10

<210> SEQ ID NO: 43

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 43

Phe Phe Phe Arg Phe Phe Phe Asp Phe Glu

1 5 10

<210> SEQ ID NO: 44

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 44

Phe Phe Phe Arg Phe Phe Phe Asn Phe Asn

1 5 10

<210> SEQ ID NO: 45

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 45

Phe Phe Phe His Phe Phe Phe Glu Phe Gln

1 5 10

<210> SEQ ID NO: 46

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 46

Phe Phe Phe His Phe Phe Phe Asn Phe Glu

1 5 10

<210> SEQ ID NO: 47

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 47

Phe Phe Phe His Phe Phe Phe Glu Phe Asn

1 5 10

<210> SEQ ID NO: 48

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 48

Glu Phe Asn Phe Phe Phe His Phe Phe Phe

1 5 10

<210> SEQ ID NO: 49

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 49

Phe Phe Phe Arg Phe Phe Phe Glu Phe Asn

1 5 10

<210> SEQ ID NO: 50

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 50

Phe Phe Phe His Phe Phe Phe Glu Phe Glu

1 5 10

<210> SEQ ID NO: 51

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 51

Gln Phe Glu Phe Phe Phe His Phe Phe Phe

1 5 10

<210> SEQ ID NO: 52

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 52

Phe Phe Phe His Phe Phe Phe Glu Phe Asp

1 5 10

<210> SEQ ID NO: 53

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 53

Phe Phe Phe His Phe Phe Phe Asp Phe Glu

1 5 10

<210> SEQ ID NO: 54

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 54

Tyr Tyr Tyr Arg Tyr Tyr Tyr Glu Tyr Gln

1 5 10

<210> SEQ ID NO: 55

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 55

Asn Phe Glu Phe Phe Phe His Phe Phe Phe

1 5 10

<210> SEQ ID NO: 56

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 56

Phe Phe Phe Lys Phe Phe Phe Lys Phe Glu

1 5 10

<210> SEQ ID NO: 57

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 57

Glu Phe Asp Phe Phe Phe Arg Phe Phe Phe

1 5 10

<210> SEQ ID NO: 58

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 58

Phe Phe Phe His Phe Phe Phe Asp Phe Asp

1 5 10

<210> SEQ ID NO: 59

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 59

Phe Phe Phe His Phe Phe Phe Asn Phe Asn

1 5 10

<210> SEQ ID NO: 60

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 60

Phe Phe Phe Arg Phe Phe Phe Asp Phe Asp

1 5 10

<210> SEQ ID NO: 61

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 61

Phe Phe Phe Lys Phe Phe Phe Lys Phe Asn

1 5 10

<210> SEQ ID NO: 62

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 62

Phe Phe Phe Lys Phe Phe Phe Glu Phe Glu

1 5 10

<210> SEQ ID NO: 63

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 63

Phe Phe Phe Glu Phe Phe Phe Lys Phe Glu

1 5 10

<210> SEQ ID NO: 64

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 64

Phe Phe Phe Gln Phe Phe Phe Gln Phe Gln

1 5 10

<210> SEQ ID NO: 65

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 65

Phe Phe Phe Lys Phe Phe Phe Gln Phe Gln

1 5 10

<210> SEQ ID NO: 66

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 66

Phe Phe Phe Lys Phe Phe Phe Asn Phe Asn

1 5 10

<210> SEQ ID NO: 67

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 67

Phe Phe Phe Asn Phe Phe Phe Asn Phe Asn

1 5 10

<210> SEQ ID NO: 68

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 68

Phe Phe Phe Lys Phe Phe Phe Glu Phe Gln

1 5 10

<210> SEQ ID NO: 69

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 69

Phe Phe Phe Lys Phe Phe Phe Lys Phe Gln

1 5 10

<210> SEQ ID NO: 70

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 70

Phe Phe Phe Lys Phe Phe Phe Gln Phe Lys

1 5 10

<210> SEQ ID NO: 71

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 71

Phe Phe Phe Lys Phe Phe Phe Lys Phe Asp

1 5 10

<210> SEQ ID NO: 72

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 72

Phe Phe Phe Lys Phe Phe Phe Asp Phe Asp

1 5 10

<210> SEQ ID NO: 73

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 73

Phe Phe Phe Asn Phe Phe Phe Lys Phe Asn

1 5 10

<210> SEQ ID NO: 74

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 74

Phe Phe Phe Asp Phe Phe Phe Asp Phe Asp

1 5 10

<210> SEQ ID NO: 75

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 75

Phe Phe Phe Lys Phe Phe Phe Glu Phe Lys

1 5 10

<210> SEQ ID NO: 76

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 76

Phe Phe Phe Lys Phe Phe Phe Asp Phe Lys

1 5 10

<210> SEQ ID NO: 77

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 77

Phe Phe Phe Glu Phe Phe Phe Glu Phe Glu

1 5 10

<210> SEQ ID NO: 78

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 78

Phe Phe Phe Asp Phe Phe Phe Lys Phe Asp

1 5 10

<210> SEQ ID NO: 79

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 79

Phe Phe Phe Lys Phe Phe Phe Lys Phe Lys

1 5 10

<210> SEQ ID NO: 80

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 80

Phe Phe Phe Glu Phe Phe Phe Lys Phe Lys

1 5 10

<210> SEQ ID NO: 81

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 81

Phe Phe Phe Gln Phe Phe Phe Lys Phe Lys

1 5 10

<210> SEQ ID NO: 82

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 82

Phe Phe Phe Lys Phe Phe Phe Asn Phe Lys

1 5 10

<210> SEQ ID NO: 83

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 83

Phe Phe Phe Asn Phe Phe Phe Lys Phe Lys

1 5 10

<210> SEQ ID NO: 84

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 84

Phe Phe Phe Gln Phe Phe Phe Lys Phe Gln

1 5 10

<210> SEQ ID NO: 85

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 85

Phe Phe Phe Asp Phe Phe Phe Lys Phe Lys

1 5 10

<210> SEQ ID NO: 86

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 86

Leu Leu Leu Arg Leu Leu Leu Glu Leu Gln

1 5 10

<210> SEQ ID NO: 87

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 87

Phe Val Phe Lys Phe Val Phe Lys Phe Val

1 5 10

<210> SEQ ID NO: 88

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 88

Cys Cys Cys Arg Cys Cys Cys Glu Cys Gln

1 5 10

<210> SEQ ID NO: 89

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 89

Met Met Met Arg Met Met Met Glu Met Gln

1 5 10

<210> SEQ ID NO: 90

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 90

Val Val Val Arg Val Val Val Glu Val Gln

1 5 10

<210> SEQ ID NO: 91

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 91

Ile Ile Ile Arg Ile Ile Ile Glu Ile Gln

1 5 10

<210> SEQ ID NO: 92

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 92

Gly Gly Gly Arg Gly Gly Gly Glu Gly Gln

1 5 10

<210> SEQ ID NO: 93

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 93

Pro Pro Pro Arg Pro Pro Pro Glu Pro Gln

1 5 10

<210> SEQ ID NO: 94

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 94

Thr Thr Thr Arg Thr Thr Thr Glu Thr Gln

1 5 10

<210> SEQ ID NO: 95

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 95

Ala Ala Ala Arg Ala Ala Ala Glu Ala Gln

1 5 10

<210> SEQ ID NO: 96

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 96

Ala Ala Ala Lys Ala Ala Ala Lys Ala Ala

1 5 10

<210> SEQ ID NO: 97

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 97

Ala Ala Ala Glu Ala Ala Ala Glu Ala Glu

1 5 10

<210> SEQ ID NO: 98

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 98

Ser Ser Ser Arg Ser Ser Ser Glu Ser Gln

1 5 10

<210> SEQ ID NO: 99

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 99

His His His Arg His His His Glu His Gln

1 5 10

<210> SEQ ID NO: 100

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 100

Arg Arg Arg Arg Arg Arg Arg Glu Arg Gln

1 5 10

<210> SEQ ID NO: 101

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 101

Gln Gln Gln Arg Gln Gln Gln Glu Gln Gln

1 5 10

<210> SEQ ID NO: 102

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 102

Glu Glu Glu Arg Glu Glu Glu Glu Glu Gln

1 5 10

<210> SEQ ID NO: 103

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 103

Asn Asn Asn Arg Asn Asn Asn Glu Asn Gln

1 5 10

<210> SEQ ID NO: 104

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 104

Asp Asp Asp Arg Asp Asp Asp Glu Asp Gln

1 5 10

<210> SEQ ID NO: 105

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 105

Lys Lys Lys Arg Lys Lys Lys Glu Lys Gln

1 5 10

<210> SEQ ID NO: 106

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 106

Phe Phe Gln Lys Phe Phe Lys Arg Trp Arg

1 5 10

<210> SEQ ID NO: 107

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 107

Phe Phe Arg Lys Phe Phe Lys Arg Phe Arg

1 5 10

<210> SEQ ID NO: 108

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 108

Arg Phe Arg Lys Phe Phe Lys Arg Phe Phe

1 5 10

<210> SEQ ID NO: 109

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 109

Arg Phe Arg Lys Phe Phe Lys Gln Phe Phe

1 5 10

<210> SEQ ID NO: 110

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 110

Phe Phe Gln Lys Phe Phe Lys Arg Phe Arg

1 5 10

<210> SEQ ID NO: 111

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 111

Arg Trp Arg Lys Phe Phe Lys Gln Phe Phe

1 5 10

<210> SEQ ID NO: 112

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 112

Phe Phe Glu His Phe Trp Lys Glu Phe Asn

1 5 10

<210> SEQ ID NO: 113

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 113

Phe Phe Gln His Phe Trp Lys Gln Phe Asn

1 5 10

<210> SEQ ID NO: 114

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 114

Gln Phe Asn His Phe Phe Lys Glu Phe Phe

1 5 10

<210> SEQ ID NO: 115

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 115

Phe Phe Asp Lys Phe Phe His Asp Phe Gln

1 5 10

<210> SEQ ID NO: 116

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 116

Gln Phe Asp His Phe Phe Lys Asp Phe Phe

1 5 10

<210> SEQ ID NO: 117

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 117

Phe Phe Glu Lys Phe Phe His Asn Phe Gln

1 5 10

<210> SEQ ID NO: 118

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 118

Asn Phe Glu Lys Trp Phe His Glu Phe Phe

1 5 10

<210> SEQ ID NO: 119

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 119

Leu Phe Arg Arg Ala Phe Lys Gln Leu Asp

1 5 10

<210> SEQ ID NO: 120

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 120

Asn Phe Gln Lys Trp Phe His Gln Phe Phe

1 5 10

<210> SEQ ID NO: 121

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 121

Lys Phe Arg Lys Ala Phe Lys Arg Phe Phe

1 5 10

<210> SEQ ID NO: 122

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 122

Phe Phe Arg Lys Phe Ala Lys Arg Phe Lys

1 5 10

<210> SEQ ID NO: 123

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 123

Phe Phe Lys Lys Phe Phe Lys Lys Phe Lys

1 5 10

<210> SEQ ID NO: 124

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 124

Lys Phe Lys Lys Phe Phe Lys Lys Phe Phe

1 5 10

<210> SEQ ID NO: 125

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 125

Lys Ala Arg Lys Ala Phe Lys Arg Phe Phe

1 5 10

<210> SEQ ID NO: 126

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 126

Trp Val Lys Asp Ala Met Gln His Leu Asp

1 5 10

<210> SEQ ID NO: 127

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 127

Phe Phe Lys Lys Phe Ala Lys Lys Phe Lys

1 5 10

<210> SEQ ID NO: 128

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 128

Phe Ala Glu Lys Phe Phe Lys Asn Phe Lys

1 5 10

<210> SEQ ID NO: 129

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 129

Lys Phe Asn Lys Phe Phe Lys Glu Ala Phe

1 5 10

<210> SEQ ID NO: 130

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 130

Phe Ala Lys Gln Phe Phe Asn Lys Phe Lys

1 5 10

<210> SEQ ID NO: 131

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 131

Lys Phe Asn Lys Ala Phe Lys Gln Ala Phe

1 5 10

<210> SEQ ID NO: 132

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 132

His Tyr Trp His

1

<210> SEQ ID NO: 133

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 133

Phe Ala Gln Lys Phe Phe Lys Asp Phe Lys

1 5 10

<210> SEQ ID NO: 134

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 134

Phe Ala Glu Glu Phe Ala Glu Glu Phe Glu

1 5 10

<210> SEQ ID NO: 135

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 135

Lys Phe Lys Lys Phe Phe Lys Lys Ala Phe

1 5 10

<210> SEQ ID NO: 136

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 136

Lys Phe Lys Asn Phe Phe Gln Lys Ala Phe

1 5 10

<210> SEQ ID NO: 137

<211> LENGTH: 433

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 137

Met Val Trp Lys Val Ala Val Phe Leu Ser Val Ala Leu Gly Ile Gly

1 5 10 15

Ala Ile Pro Ile Asp Asp Pro Glu Asp Gly Gly Lys His Trp Val Val

20 25 30

Ile Val Ala Gly Ser Asn Gly Trp Tyr Asn Tyr Arg His Gln Ala Asp

35 40 45

Ala Cys His Ala Tyr Gln Ile Ile His Arg Asn Gly Ile Pro Asp Glu

50 55 60

Gln Ile Val Val Met Met Tyr Asp Asp Ile Ala Tyr Ser Glu Asp Asn

65 70 75 80

Pro Thr Pro Gly Ile Val Ile Asn Arg Pro Asn Gly Thr Asp Val Tyr

85 90 95

Gln Gly Val Pro Lys Asp Tyr Thr Gly Glu Asp Val Thr Pro Gln Asn

100 105 110

Phe Leu Ala Val Leu Arg Gly Asp Ala Glu Ala Val Lys Gly Ile Gly

115 120 125

Ser Gly Lys Val Leu Lys Ser Gly Pro Gln Asp His Val Phe Ile Tyr

130 135 140

Phe Thr Asp His Gly Ser Thr Gly Ile Leu Val Phe Pro Asn Glu Asp

145 150 155 160

Leu His Val Lys Asp Leu Asn Glu Thr Ile His Tyr Met Tyr Lys His

165 170 175

Lys Met Tyr Arg Lys Met Val Phe Tyr Ile Glu Ala Cys Glu Ser Gly

180 185 190

Ser Met Met Asn His Leu Pro Asp Asn Ile Asn Val Tyr Ala Thr Thr

195 200 205

Ala Ala Asn Pro Arg Glu Ser Ser Tyr Ala Cys Tyr Tyr Asp Glu Lys

210 215 220

Arg Ser Thr Tyr Leu Gly Asp Trp Tyr Ser Val Asn Trp Met Glu Asp

225 230 235 240

Ser Asp Val Glu Asp Leu Thr Lys Glu Thr Leu His Lys Gln Tyr His

245 250 255

Leu Val Lys Ser His Thr Asn Thr Ser His Val Met Gln Tyr Gly Asn

260 265 270

Lys Thr Ile Ser Thr Met Lys Val Met Gln Phe Gln Gly Met Lys Arg

275 280 285

Lys Ala Ser Ser Pro Val Pro Leu Pro Pro Val Thr His Leu Asp Leu

290 295 300

Thr Pro Ser Pro Asp Val Pro Leu Thr Ile Met Lys Arg Lys Leu Met

305 310 315 320

Asn Thr Asn Asp Leu Glu Glu Ser Arg Gln Leu Thr Glu Glu Ile Gln

325 330 335

Arg His Leu Asp Ala Arg His Leu Ile Glu Lys Ser Val Arg Lys Ile

340 345 350

Val Ser Leu Leu Ala Ala Ser Glu Ala Glu Val Glu Gln Leu Leu Ser

355 360 365

Glu Arg Ala Pro Leu Thr Gly His Ser Cys Tyr Pro Glu Ala Leu Leu

370 375 380

His Phe Arg Thr His Cys Phe Asn Trp His Ser Pro Thr Tyr Glu Tyr

385 390 395 400

Ala Leu Arg His Leu Tyr Val Leu Val Asn Leu Cys Glu Lys Pro Tyr

405 410 415

Pro Leu His Arg Ile Lys Leu Ser Met Asp His Val Cys Leu Gly His

420 425 430

Tyr

<210> SEQ ID NO: 138

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 138

Phe Ala Lys Gln Phe Ala Asn Lys Phe Lys

1 5 10

<210> SEQ ID NO: 139

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 139

Lys Phe Lys Asn Ala Phe Gln Lys Ala Phe

1 5 10

<210> SEQ ID NO: 140

<211> LENGTH: 360

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 140

Met Ser Asp Ser Lys Glu Pro Arg Leu Gln Gln Leu Gly Leu Leu Val

1 5 10 15

Ser Lys Val Pro Ser Ser Ile Ser Gln Glu Gln Ser Arg Gln Asp Ala

20 25 30

Ile Tyr Gln Asn Leu Thr Gln Leu Lys Ala Ala Val Gly Glu Leu Ser

35 40 45

Glu Lys Ser Lys Leu Gln Glu Ile Tyr Gln Glu Leu Thr Gln Leu Lys

50 55 60

Ala Ala Val Gly Glu Leu Pro Glu Lys Ser Lys Leu Gln Glu Ile Tyr

65 70 75 80

Gln Glu Leu Thr Arg Leu Lys Ala Ala Val Gly Glu Leu Pro Glu Lys

85 90 95

Ser Lys Leu Gln Glu Ile Tyr Gln Glu Leu Thr Trp Leu Lys Ala Ala

100 105 110

Val Gly Glu Leu Pro Glu Lys Ser Lys Met Gln Glu Ile Tyr Gln Glu

115 120 125

Leu Thr Arg Leu Lys Ala Ala Val Gly Glu Leu Pro Glu Lys Ser Lys

130 135 140

Gln Gln Glu Ile Tyr Gln Glu Leu Thr Arg Leu Lys Ala Ala Val Gly

145 150 155 160

Glu Leu Pro Glu Lys Ser Lys Gln Gln Glu Ile Tyr Gln Glu Leu Thr

165 170 175

Arg Leu Lys Ala Ala Val Gly Glu Leu Pro Glu Lys Ser Lys Gln Gln

180 185 190

Glu Ile Tyr Gln Glu Leu Thr Gln Leu Lys Ala Ala Val Glu Arg Leu

195 200 205

Cys His Pro Cys Pro Trp Glu Trp Thr Phe Phe Gln Gly Asn Cys Tyr

210 215 220

Phe Met Ser Asn Ser Gln Arg Asn Trp His Asp Ser Ile Thr Ala Cys

225 230 235 240

Lys Glu Val Gly Ala Gln Leu Val Val Ile Lys Ser Ala Glu Glu Gln

245 250 255

Asn Phe Leu Gln Leu Gln Ser Ser Arg Ser Asn Arg Phe Thr Trp Met

260 265 270

Gly Leu Ser Asp Leu Asn Gln Glu Gly Thr Trp Gln Trp Val Asp Gly

275 280 285

Ser Pro Leu Leu Pro Ser Phe Lys Gln Tyr Trp Asn Arg Gly Glu Pro

290 295 300

Asn Asn Val Gly Glu Glu Asp Cys Ala Glu Phe Ser Gly Asn Gly Trp

305 310 315 320

Asn Asp Asp Lys Cys Asn Leu Ala Lys Phe Trp Ile Cys Lys Lys Ser

325 330 335

Ala Ala Ser Cys Ser Arg Asp Glu Glu Gln Phe Leu Ser Pro Ala Pro

340 345 350

Ala Thr Pro Asn Pro Pro Pro Ala

355 360

<210> SEQ ID NO: 141

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 141

Phe Ala Lys Lys Phe Phe Lys Lys Phe Lys

1 5 10

<210> SEQ ID NO: 142

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 142

Lys Phe Lys Lys Ala Phe Lys Lys Phe Phe

1 5 10

<210> SEQ ID NO: 143

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 143

Phe Ala Glu Lys Phe Ala Glu Lys Phe Glu

1 5 10

<210> SEQ ID NO: 144

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 144

Asp Leu His Gln Met Ala Asp Lys Val Trp

1 5 10

<210> SEQ ID NO: 145

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 145

Lys Ala Arg Lys Ala Ala Lys Arg Phe Phe

1 5 10

<210> SEQ ID NO: 146

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 146

Phe Ala Lys Asn Phe Ala Lys Lys Phe Lys

1 5 10

<210> SEQ ID NO: 147

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 147

Phe Ala Glu Lys Phe Ala Lys Asn Phe Lys

1 5 10

<210> SEQ ID NO: 148

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 148

Lys Phe Lys Lys Ala Phe Lys Lys Ala Phe

1 5 10

<210> SEQ ID NO: 149

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 149

Phe Ala Lys Asn Phe Ala Lys Asn Phe Lys

1 5 10

<210> SEQ ID NO: 150

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 150

Phe Ala Lys Glu Phe Ala Lys Glu Phe Glu

1 5 10

<210> SEQ ID NO: 151

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 151

Lys Phe Asp Lys Ala Phe Lys Gln Ala Phe

1 5 10

<210> SEQ ID NO: 152

<211> LENGTH: 335

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 152

Met Leu Gly Ile Trp Thr Leu Leu Pro Leu Val Leu Thr Ser Val Ala

1 5 10 15

Arg Leu Ser Ser Lys Ser Val Asn Ala Gln Val Thr Asp Ile Asn Ser

20 25 30

Lys Gly Leu Glu Leu Arg Lys Thr Val Thr Thr Val Glu Thr Gln Asn

35 40 45

Leu Glu Gly Leu His His Asp Gly Gln Phe Cys His Lys Pro Cys Pro

50 55 60

Pro Gly Glu Arg Lys Ala Arg Asp Cys Thr Val Asn Gly Asp Glu Pro

65 70 75 80

Asp Cys Val Pro Cys Gln Glu Gly Lys Glu Tyr Thr Asp Lys Ala His

85 90 95

Phe Ser Ser Lys Cys Arg Arg Cys Arg Leu Cys Asp Glu Gly His Gly

100 105 110

Leu Glu Val Glu Ile Asn Cys Thr Arg Thr Gln Asn Thr Lys Cys Arg

115 120 125

Cys Lys Pro Asn Phe Phe Cys Asn Ser Thr Val Cys Glu His Cys Asp

130 135 140

Pro Cys Thr Lys Cys Glu His Gly Ile Ile Lys Glu Cys Thr Leu Thr

145 150 155 160

Ser Asn Thr Lys Cys Lys Glu Glu Gly Ser Arg Ser Asn Leu Gly Trp

165 170 175

Leu Cys Leu Leu Leu Leu Pro Ile Pro Leu Ile Val Trp Val Lys Arg

180 185 190

Lys Glu Val Gln Lys Thr Cys Arg Lys His Arg Lys Glu Asn Gln Gly

195 200 205

Ser His Glu Ser Pro Thr Leu Asn Pro Glu Thr Val Ala Ile Asn Leu

210 215 220

Ser Asp Val Asp Leu Ser Lys Tyr Ile Thr Thr Ile Ala Gly Val Met

225 230 235 240

Thr Leu Ser Gln Val Lys Gly Phe Val Arg Lys Asn Gly Val Asn Glu

245 250 255

Ala Lys Ile Asp Glu Ile Lys Asn Asp Asn Val Gln Asp Thr Ala Glu

260 265 270

Gln Lys Val Gln Leu Leu Arg Asn Trp His Gln Leu His Gly Lys Lys

275 280 285

Glu Ala Tyr Asp Thr Leu Ile Lys Asp Leu Lys Lys Ala Asn Leu Cys

290 295 300

Thr Leu Ala Glu Lys Ile Gln Thr Ile Ile Leu Lys Asp Ile Thr Ser

305 310 315 320

Asp Ser Glu Asn Ser Asn Phe Arg Asn Glu Ile Gln Ser Leu Val

325 330 335

<210> SEQ ID NO: 153

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 153

Phe Ala Glu Lys Phe Ala Lys Lys Phe Lys

1 5 10

<210> SEQ ID NO: 154

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 154

Phe Ala Glu Lys Phe Ala Glu Lys Phe Lys

1 5 10

<210> SEQ ID NO: 155

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 155

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys

1 5 10

<210> SEQ ID NO: 156

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 156

Phe Ala Lys Asn Phe Ala Lys Asn Phe Asn

1 5 10

<210> SEQ ID NO: 157

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 157

Phe Ala Gln Lys Phe Ala Lys Asn Phe Lys

1 5 10

<210> SEQ ID NO: 158

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 158

Phe Ala Asn Asn Phe Ala Asn Asn Phe Asn

1 5 10

<210> SEQ ID NO: 159

<211> LENGTH: 198

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 159

Met Gln Ile Pro Gln Ala Pro Trp Pro Val Val Trp Ala Val Leu Gln

1 5 10 15

Leu Gly Trp Arg Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp

20 25 30

Asn Pro Pro Thr Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp

35 40 45

Asn Ala Thr Phe Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val

50 55 60

Leu Asn Trp Tyr Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala

65 70 75 80

Ala Phe Pro Glu Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg

85 90 95

Val Thr Gln Leu Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg

100 105 110

Ala Arg Arg Asn Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu

115 120 125

Ala Pro Lys Ala Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val

130 135 140

Thr Glu Arg Arg Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro

145 150 155 160

Arg Pro Ala Gly Gln Phe Gln Thr Leu Val Val Gly Val Val Gly Gly

165 170 175

Leu Leu Gly Ser Leu Val Leu Leu Val Trp Val Leu Ala Val Ile Cys

180 185 190

Ser Arg Ala Ala Arg Gly

195

<210> SEQ ID NO: 160

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 160

Phe Ala Asn Lys Phe Ala Asn Lys Phe Asn

1 5 10

<210> SEQ ID NO: 161

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 161

Phe Ala Asn Lys Phe Ala Lys Lys Phe Lys

1 5 10

<210> SEQ ID NO: 162

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 162

Phe Ala Gln Lys Phe Ala Lys Asp Phe Lys

1 5 10

<210> SEQ ID NO: 163

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 163

Phe Ala Lys Glu Phe Ala Lys Glu Phe Lys

1 5 10

<210> SEQ ID NO: 164

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 164

Phe Ala Asn Lys Phe Ala Asn Lys Phe Lys

1 5 10

<210> SEQ ID NO: 165

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 165

Lys Phe Asp Lys Phe Phe Lys Gln Ala Phe

1 5 10

<210> SEQ ID NO: 166

<211> LENGTH: 435

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 166

Met Ala Ala Ser Ser Leu Glu Gln Lys Leu Ser Arg Leu Glu Ala Lys

1 5 10 15

Leu Lys Gln Glu Asn Arg Glu Ala Arg Arg Arg Ile Asp Leu Asn Leu

20 25 30

Asp Ile Ser Pro Gln Arg Pro Arg Pro Ile Ile Val Ile Thr Leu Ser

35 40 45

Pro Ala Pro Ala Pro Ser Gln Arg Ala Ala Leu Gln Leu Pro Leu Ala

50 55 60

Asn Asp Gly Gly Ser Arg Ser Pro Ser Ser Glu Ser Ser Pro Gln His

65 70 75 80

Pro Thr Pro Pro Ala Arg Pro Arg His Met Leu Gly Leu Pro Ser Thr

85 90 95

Leu Phe Thr Pro Arg Ser Met Glu Ser Ile Glu Ile Asp Gln Lys Leu

100 105 110

Gln Glu Ile Met Lys Gln Thr Gly Tyr Leu Thr Ile Gly Gly Gln Arg

115 120 125

Tyr Gln Ala Glu Ile Asn Asp Leu Glu Asn Leu Gly Glu Met Gly Ser

130 135 140

Gly Thr Cys Gly Gln Val Trp Lys Met Arg Phe Arg Lys Thr Gly His

145 150 155 160

Val Ile Ala Val Lys Gln Met Arg Arg Ser Gly Asn Lys Glu Glu Asn

165 170 175

Lys Arg Ile Leu Met Asp Leu Asp Val Val Leu Lys Ser His Asp Cys

180 185 190

Pro Tyr Ile Val Gln Cys Phe Gly Thr Phe Ile Thr Asn Thr Asp Val

195 200 205

Phe Ile Ala Met Glu Leu Met Gly Thr Cys Ala Glu Lys Leu Lys Lys

210 215 220

Arg Met Gln Gly Pro Ile Pro Glu Arg Ile Leu Gly Lys Met Thr Val

225 230 235 240

Ala Ile Val Lys Ala Leu Tyr Tyr Leu Lys Glu Lys His Gly Val Ile

245 250 255

His Arg Asp Val Lys Pro Ser Asn Ile Leu Leu Asp Glu Arg Gly Gln

260 265 270

Ile Lys Leu Cys Asp Phe Gly Ile Ser Gly Arg Leu Val Asp Ser Lys

275 280 285

Ala Lys Thr Arg Ser Ala Gly Cys Ala Ala Tyr Met Ala Pro Glu Arg

290 295 300

Ile Asp Pro Pro Asp Pro Thr Lys Pro Asp Tyr Asp Ile Arg Ala Asp

305 310 315 320

Val Trp Ser Leu Gly Ile Ser Leu Val Glu Leu Ala Thr Gly Gln Phe

325 330 335

Pro Tyr Lys Asn Cys Lys Thr Asp Phe Glu Val Leu Thr Lys Val Leu

340 345 350

Gln Glu Glu Pro Pro Leu Leu Pro Gly His Met Gly Phe Ser Gly Asp

355 360 365

Phe Gln Ser Phe Val Lys Asp Cys Leu Thr Lys Asp His Arg Lys Arg

370 375 380

Pro Lys Tyr Asn Lys Leu Leu Glu His Ser Phe Ile Lys Arg Tyr Glu

385 390 395 400

Thr Leu Glu Val Asp Val Ala Ser Trp Phe Lys Asp Val Met Ala Lys

405 410 415

Thr Glu Ser Pro Arg Thr Ser Gly Val Leu Ser Gln Pro His Leu Pro

420 425 430

Phe Phe Arg

435

<210> SEQ ID NO: 167

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 167

Lys Phe Asn Lys Ala Phe Lys Glu Ala Phe

1 5 10

<210> SEQ ID NO: 168

<211> LENGTH: 888

<212> TYPE: PRT

<213> ORGANISM: Saccharomyces cerevisiae

<400> SEQENCE: 168

Met Tyr Val Tyr Lys Arg Asp Gly Arg Lys Glu Pro Val Gln Phe Asp

1 5 10 15

Lys Ile Thr Ala Arg Ile Ser Arg Leu Cys Tyr Gly Leu Asp Pro Lys

20 25 30

His Ile Asp Ala Val Lys Val Thr Gln Arg Ile Ile Ser Gly Val Tyr

35 40 45

Glu Gly Val Thr Thr Ile Glu Leu Asp Asn Leu Ala Ala Glu Thr Cys

50 55 60

Ala Tyr Met Thr Thr Val His Pro Asp Tyr Ala Thr Leu Ala Ala Arg

65 70 75 80

Ile Ala Ile Ser Asn Leu His Lys Gln Thr Thr Lys Gln Phe Ser Lys

85 90 95

Val Val Glu Asp Leu Tyr Arg Tyr Val Asn Ala Ala Thr Gly Lys Pro

100 105 110

Ala Pro Met Ile Ser Asp Asp Val Tyr Asn Ile Val Met Glu Asn Lys

115 120 125

Asp Lys Leu Asn Ser Ala Ile Val Tyr Asp Arg Asp Phe Gln Tyr Ser

130 135 140

Tyr Phe Gly Phe Lys Thr Leu Glu Arg Ser Tyr Leu Leu Arg Ile Asn

145 150 155 160

Gly Gln Val Ala Glu Arg Pro Gln His Leu Ile Met Arg Val Ala Leu

165 170 175

Gly Ile His Gly Arg Asp Ile Glu Ala Ala Leu Glu Thr Tyr Asn Leu

180 185 190

Met Ser Leu Lys Tyr Tyr Thr His Ala Ser Pro Thr Leu Phe Asn Ala

195 200 205

Gly Thr Pro Lys Pro Gln Met Ser Ser Cys Phe Leu Val Ala Met Lys

210 215 220

Glu Asp Ser Ile Glu Gly Ile Tyr Asp Thr Leu Lys Glu Cys Ala Leu

225 230 235 240

Ile Ser Lys Thr Ala Gly Gly Ile Gly Leu His Ile His Asn Ile Arg

245 250 255

Ser Thr Gly Ser Tyr Ile Ala Gly Thr Asn Gly Thr Ser Asn Gly Leu

260 265 270

Ile Pro Met Ile Arg Val Phe Asn Asn Thr Ala Arg Tyr Val Asp Gln

275 280 285

Gly Gly Asn Lys Arg Pro Gly Ala Phe Ala Leu Tyr Leu Glu Pro Trp

290 295 300

His Ala Asp Ile Phe Asp Phe Ile Asp Ile Arg Lys Asn His Gly Lys

305 310 315 320

Glu Glu Ile Arg Ala Arg Asp Leu Phe Pro Ala Leu Trp Ile Pro Asp

325 330 335

Leu Phe Met Lys Arg Val Glu Glu Asn Gly Thr Trp Thr Leu Phe Ser

340 345 350

Pro Thr Ser Ala Pro Gly Leu Ser Asp Cys Tyr Gly Asp Glu Phe Glu

355 360 365

Ala Leu Tyr Thr Arg Tyr Glu Lys Glu Gly Arg Gly Lys Thr Ile Lys

370 375 380

Ala Gln Lys Leu Trp Tyr Ser Ile Leu Glu Ala Gln Thr Glu Thr Gly

385 390 395 400

Thr Pro Phe Val Val Tyr Lys Asp Ala Cys Asn Arg Lys Ser Asn Gln

405 410 415

Lys Asn Leu Gly Val Ile Lys Ser Ser Asn Leu Cys Cys Glu Ile Val

420 425 430

Glu Tyr Ser Ala Pro Asp Glu Thr Ala Val Cys Asn Leu Ala Ser Val

435 440 445

Ala Leu Pro Ala Phe Ile Glu Thr Ser Glu Asp Gly Lys Thr Ser Thr

450 455 460

Tyr Asn Phe Lys Lys Leu His Glu Ile Ala Lys Val Val Thr Arg Asn

465 470 475 480

Leu Asn Arg Val Ile Asp Arg Asn Tyr Tyr Pro Val Glu Glu Ala Arg

485 490 495

Lys Ser Asn Met Arg His Arg Pro Ile Ala Leu Gly Val Gln Gly Leu

500 505 510

Ala Asp Thr Phe Met Leu Leu Arg Leu Pro Phe Asp Ser Glu Glu Ala

515 520 525

Arg Leu Leu Asn Ile Gln Ile Phe Glu Thr Ile Tyr His Ala Ser Met

530 535 540

Glu Ala Ser Cys Glu Leu Ala Gln Lys Asp Gly Pro Tyr Glu Thr Phe

545 550 555 560

Gln Gly Ser Pro Ala Ser Gln Gly Ile Leu Gln Phe Asp Met Trp Asp

565 570 575

Gln Lys Pro Tyr Gly Met Trp Asp Trp Asp Thr Leu Arg Lys Asp Ile

580 585 590

Met Lys His Gly Ile Arg Asn Ser Leu Thr Met Ala Pro Met Pro Thr

595 600 605

Ala Ser Thr Ser Gln Ile Leu Gly Tyr Asn Glu Cys Phe Glu Pro Val

610 615 620

Thr Ser Asn Met Tyr Ser Arg Arg Val Leu Ser Gly Glu Phe Gln Val

625 630 635 640

Val Asn Pro Tyr Leu Leu Arg Asp Leu Val Asp Leu Gly Ile Trp Asp

645 650 655

Glu Gly Met Lys Gln Tyr Leu Ile Thr Gln Asn Gly Ser Ile Gln Gly

660 665 670

Leu Pro Asn Val Pro Gln Glu Leu Lys Asp Leu Tyr Lys Thr Val Trp

675 680 685

Glu Ile Ser Gln Lys Thr Ile Ile Asn Met Ala Ala Asp Arg Ser Val

690 695 700

Tyr Ile Asp Gln Ser His Ser Leu Asn Leu Phe Leu Arg Ala Pro Thr

705 710 715 720

Met Gly Lys Leu Thr Ser Met His Phe Tyr Gly Trp Lys Lys Gly Leu

725 730 735

Lys Thr Gly Met Tyr Tyr Leu Arg Thr Gln Ala Ala Ser Ala Ala Ile

740 745 750

Gln Phe Thr Ile Asp Gln Lys Ile Ala Asp Gln Ala Thr Glu Asn Val

755 760 765

Ala Asp Ile Ser Asn Leu Lys Arg Pro Ser Tyr Met Pro Ser Ser Ala

770 775 780

Ser Tyr Ala Ala Ser Asp Phe Val Pro Ala Ala Val Thr Ala Asn Ala

785 790 795 800

Thr Ile Pro Ser Leu Asp Ser Ser Ser Glu Ala Ser Arg Glu Ala Ser

805 810 815

Pro Ala Pro Thr Gly Ser His Ser Leu Thr Lys Gly Met Ala Glu Leu

820 825 830

Asn Val Gln Glu Ser Lys Val Glu Val Pro Glu Val Pro Ala Pro Thr

835 840 845

Lys Asn Glu Glu Lys Ala Ala Pro Ile Val Asp Asp Glu Glu Thr Glu

850 855 860

Phe Asp Ile Tyr Asn Ser Lys Val Ile Ala Cys Ala Ile Asp Asn Pro

865 870 875 880

Glu Ala Cys Glu Met Cys Ser Gly

885

<210> SEQ ID NO: 169

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 169

Phe Ala Lys Glu Phe Ala Lys Lys Phe Lys

1 5 10

<210> SEQ ID NO: 170

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 170

Lys Ala Arg Lys Ala Ala Lys Arg Ala Phe

1 5 10

<210> SEQ ID NO: 171

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 171

Lys Ala Arg Lys Ala Ala Lys Arg Ala Ala

1 5 10

<210> SEQ ID NO: 172

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 172

Ala Ala Glu Glu Ala Ala Glu Glu Ala Glu

1 5 10

<210> SEQ ID NO: 173

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 173

Ala Ala Lys Lys Ala Ala Lys Lys Ala Lys

1 5 10

<210> SEQ ID NO: 174

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 174

Phe Val Lys Phe Val Lys Phe Val Lys Phe

1 5 10

<210> SEQ ID NO: 175

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 175

Lys Arg Lys Ala Phe Arg Lys Phe Phe Phe

1 5 10

<210> SEQ ID NO: 176

<211> LENGTH: 9

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 176

Leu His Lys Met Tyr Asn Gln Val Trp

1 5

<210> SEQ ID NO: 177

<211> LENGTH: 9

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 177

Trp Val Gln Asn Tyr Met Lys His Leu

1 5

<210> SEQ ID NO: 178

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 178

Arg Leu Val Glu Met Met Arg Gln Ile Trp

1 5 10

<210> SEQ ID NO: 179

<211> LENGTH: 9

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 179

Phe Leu Lys Arg Leu Leu Gln Glu Ile

1 5

<210> SEQ ID NO: 180

<211> LENGTH: 8

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 180

Leu Arg Leu Leu His Arg Leu Leu

1 5

<210> SEQ ID NO: 181

<211> LENGTH: 9

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 181

Trp Val Arg Asp Ser Met Lys His Leu

1 5

<210> SEQ ID NO: 182

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 182

Lys Phe Phe Arg Lys Lys Phe Arg Phe Ala

1 5 10

<210> SEQ ID NO: 183

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 183

Trp Val Gln Arg Val Val Glu Lys Phe Leu

1 5 10

<210> SEQ ID NO: 184

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 184

Ala Phe Phe Arg Arg Phe Lys Phe Lys Lys

1 5 10

<210> SEQ ID NO: 185

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 185

Leu Phe Lys Glu Val Val Arg Gln Val Trp

1 5 10

<210> SEQ ID NO: 186

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 186

Met Asp Lys Ile Tyr Asp Gln Val Trp Lys

1 5 10

<210> SEQ ID NO: 187

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 187

Phe Val Lys Lys Phe Val Lys Lys Phe Val

1 5 10

<210> SEQ ID NO: 188

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 188

Lys Lys Phe Lys Phe Arg Arg Phe Phe Ala

1 5 10

<210> SEQ ID NO: 189

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 189

Trp Val Arg Asp Val Val Arg Ser Met Asp

1 5 10

<210> SEQ ID NO: 190

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 190

Glu Leu Ser Asn Ile Tyr Glu Arg Val Trp

1 5 10

<210> SEQ ID NO: 191

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 191

Trp Ile Gln Arg Met Met Glu Val Leu Arg

1 5 10

<210> SEQ ID NO: 192

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 192

Phe Phe Phe Lys Arg Phe Ala Lys Arg Lys

1 5 10

<210> SEQ ID NO: 193

<211> LENGTH: 9

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 193

Leu His Lys Met Ser Asp Arg Val Trp

1 5

<210> SEQ ID NO: 194

<211> LENGTH: 9

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 194

Phe Ala Lys Lys Phe Ala Lys Lys Phe

1 5

<210> SEQ ID NO: 195

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 195

Trp Val Arg Glu Tyr Ile Asn Ser Leu Glu

1 5 10

<210> SEQ ID NO: 196

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 196

Phe Phe Lys Lys Arg Phe Ala Phe Arg Lys

1 5 10

<210> SEQ ID NO: 197

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 197

Lys Trp Val Gln Asp Tyr Ile Lys Asp Met

1 5 10

<210> SEQ ID NO: 198

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 198

Ala Phe Arg Phe Lys Lys Arg Phe Phe Lys

1 5 10

<210> SEQ ID NO: 199

<211> LENGTH: 8

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 199

Leu Leu Arg His Leu Leu Arg Leu

1 5

<210> SEQ ID NO: 200

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 200

Trp Ile Lys Lys Leu Leu Glu Ser Ser Gln

1 5 10

<210> SEQ ID NO: 201

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 201

Asp Met Ser Arg Val Val Asp Arg Val Trp

1 5 10

<210> SEQ ID NO: 202

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 202

Phe Glu Glu Glu Phe Glu Glu Glu Phe Glu

1 5 10

<210> SEQ ID NO: 203

<211> LENGTH: 9

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 203

Trp Val Lys Asn Ser Ile Asn His Leu

1 5

<210> SEQ ID NO: 204

<211> LENGTH: 9

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 204

Leu Thr Lys Lys Gly Arg Arg Phe Cys

1 5

<210> SEQ ID NO: 205

<211> LENGTH: 9

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 205

Ile Glu Gln Leu Leu Arg Lys Leu Phe

1 5

<210> SEQ ID NO: 206

<211> LENGTH: 9

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 206

Leu His Asn Ile Ser Asn Lys Val Trp

1 5

<210> SEQ ID NO: 207

<211> LENGTH: 9

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 207

Cys Phe Arg Arg Gly Lys Lys Thr Leu

1 5

<210> SEQ ID NO: 208

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 208

Ile Val Arg Arg Ala Asp Arg Ala Ala Val

1 5 10

<210> SEQ ID NO: 209

<211> LENGTH: 9

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 209

Thr Val Glu Arg Phe Lys Asn Leu Ser

1 5

<210> SEQ ID NO: 210

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 210

Gln Ser Ser Glu Leu Leu Lys Lys Ile Trp

1 5 10

<210> SEQ ID NO: 211

<211> LENGTH: 9

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 211

Ser Leu Asn Lys Phe Arg Glu Val Thr

1 5

<210> SEQ ID NO: 212

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 212

Leu Ile Lys Gln Ile Val Lys Lys Leu Phe

1 5 10

<210> SEQ ID NO: 213

<211> LENGTH: 6

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 213

Lys Lys Lys Phe Phe Phe

1 5

<210> SEQ ID NO: 214

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 214

Leu Tyr Lys Lys Ile Ile Lys Lys Leu Leu

1 5 10

<210> SEQ ID NO: 215

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 215

Phe Lys Lys Lys Phe Lys Lys Lys Phe Lys

1 5 10

<210> SEQ ID NO: 216

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 216

Val Ala Ala Arg Asp Ala Arg Arg Val Ile

1 5 10

<210> SEQ ID NO: 217

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 217

Phe Leu Lys Lys Val Ile Gln Lys Ile Leu

1 5 10

<210> SEQ ID NO: 218

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 218

Leu Ile Lys Glu Ile Ile Lys Gln Val Met

1 5 10

<210> SEQ ID NO: 219

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 219

Leu Leu Lys Lys Ile Ile Lys Lys Tyr Leu

1 5 10

<210> SEQ ID NO: 220

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 220

Ala Phe Phe Glu Glu Glu Ala Glu Phe Glu

1 5 10

<210> SEQ ID NO: 221

<211> LENGTH: 9

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 221

Lys Lys Trp Val Gln Asp Ser Met Lys

1 5

<210> SEQ ID NO: 222

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 222

Asn Phe Ala Asn Lys Val Gln Glu Val Ala

1 5 10

<210> SEQ ID NO: 223

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 223

Ala Val Glu Gln Val Lys Asn Ala Phe Asn

1 5 10

<210> SEQ ID NO: 224

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 224

Met Val Gln Lys Ile Ile Glu Lys Ile Leu

1 5 10

<210> SEQ ID NO: 225

<211> LENGTH: 9

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 225

Lys Met Ser Asp Gln Val Trp Lys Lys

1 5

<210> SEQ ID NO: 226

<211> LENGTH: 9

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 226

Met Val Lys Lys Ile Ile Glu Lys Met

1 5

<210> SEQ ID NO: 227

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 227

Ala Leu Lys Lys Gln Val Ile Lys Lys Ile

1 5 10

<210> SEQ ID NO: 228

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 228

Ile Lys Lys Ile Val Gln Lys Lys Leu Ala

1 5 10

<210> SEQ ID NO: 229

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 229

Ala Phe Phe Lys Lys Lys Ala Lys Phe Lys

1 5 10

<210> SEQ ID NO: 230

<211> LENGTH: 8

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 230

Met Lys Glu Ile Ile Lys Val Met

1 5

<210> SEQ ID NO: 231

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 231

Ala Glu Glu Glu Ala Glu Glu Glu Ala Glu

1 5 10

<210> SEQ ID NO: 232

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 232

Ala Lys Lys Lys Ala Lys Lys Lys Ala Lys

1 5 10

<210> SEQ ID NO: 233

<211> LENGTH: 6

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 233

Lys Lys Lys Ala Ala Ala

1 5

<210> SEQ ID NO: 234

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 234

Lys Arg Lys Lys Arg Phe Ala Phe Phe Phe

1 5 10

<210> SEQ ID NO: 235

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 235

Arg Lys Arg Lys Phe Phe Ala Phe Phe Lys

1 5 10

<210> SEQ ID NO: 236

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 236

Phe Phe Phe Ala Phe Arg Lys Lys Arg Lys

1 5 10

<210> SEQ ID NO: 237

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 237

Phe Arg Lys Lys Arg Phe Ala Phe Phe Lys

1 5 10

<210> SEQ ID NO: 238

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 238

Phe Phe Phe Arg Arg Lys Lys Lys Phe Ala

1 5 10

<210> SEQ ID NO: 239

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 239

Lys Phe Phe Ala Phe Arg Lys Lys Arg Phe

1 5 10

<210> SEQ ID NO: 240

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 240

Lys Phe Phe Ala Phe Phe Lys Arg Lys Arg

1 5 10

<210> SEQ ID NO: 241

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 241

Lys Lys Lys Lys Lys Phe Phe Phe Phe Phe

1 5 10

<210> SEQ ID NO: 242

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 242

Ala Phe Lys Lys Lys Arg Arg Phe Phe Phe

1 5 10

<210> SEQ ID NO: 243

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 243

Lys Arg Lys Lys Arg Ala Ala Phe Phe Phe

1 5 10

<210> SEQ ID NO: 244

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 244

Lys Lys Phe Phe Ala Phe Phe Arg Lys Arg

1 5 10

<210> SEQ ID NO: 245

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 245

Arg Lys Arg Phe Phe Ala Phe Phe Lys Lys

1 5 10

<210> SEQ ID NO: 246

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 246

Lys Arg Lys Lys Arg Ala Ala Ala Phe Phe

1 5 10

<210> SEQ ID NO: 247

<211> LENGTH: 8

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 247

Lys Lys Lys Lys Phe Phe Phe Phe

1 5

<210> SEQ ID NO: 248

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 248

Lys Arg Lys Lys Arg Ala Ala Ala Ala Phe

1 5 10

<210> SEQ ID NO: 249

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 249

Lys Lys Lys Ala Phe Phe Phe Ala Lys Lys

1 5 10

<210> SEQ ID NO: 250

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 250

Lys Arg Lys Lys Arg Ala Ala Ala Ala Ala

1 5 10

<210> SEQ ID NO: 251

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 251

Lys Lys Lys Lys Lys Ala Ala Ala Ala Ala

1 5 10

<210> SEQ ID NO: 252

<211> LENGTH: 8

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 252

Lys Lys Lys Lys Ala Ala Ala Ala

1 5

<210> SEQ ID NO: 253

<211> LENGTH: 9

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 253

Phe Lys Phe Lys Phe Lys Phe Lys Phe

1 5

<210> SEQ ID NO: 254

<211> LENGTH: 8

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 254

Phe Arg Phe Lys Phe Lys Phe Arg

1 5

<210> SEQ ID NO: 255

<211> LENGTH: 8

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 255

Arg Phe Gln Phe Lys Phe Arg Phe

1 5

<210> SEQ ID NO: 256

<211> LENGTH: 7

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 256

Phe Arg Phe Lys Phe Lys Phe

1 5

<210> SEQ ID NO: 257

<211> LENGTH: 6

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 257

Phe Arg Phe Lys Phe Ala

1 5

<210> SEQ ID NO: 258

<211> LENGTH: 9

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 258

Arg Arg Phe Pro Arg Pro Pro Phe Phe

1 5

<210> SEQ ID NO: 259

<211> LENGTH: 9

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 259

Phe Phe Pro Pro Arg Pro Phe Arg Arg

1 5

<210> SEQ ID NO: 260

<211> LENGTH: 9

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 260

Leu Tyr Pro Pro Arg Pro Phe Arg Arg

1 5

<210> SEQ ID NO: 261

<211> LENGTH: 9

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 261

Arg Arg Ile Pro Arg Pro Pro Tyr Leu

1 5

<210> SEQ ID NO: 262

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 262

Pro Phe Arg Pro Pro Pro Arg Pro Arg Phe

1 5 10

<210> SEQ ID NO: 263

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 263

Pro Arg Pro Arg Pro Pro Pro Arg Phe Phe

1 5 10

<210> SEQ ID NO: 264

<211> LENGTH: 9

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 264

Phe Phe Pro Pro Lys Pro Phe Lys Lys

1 5

<210> SEQ ID NO: 265

<211> LENGTH: 9

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 265

Lys Lys Ile Pro Lys Pro Pro Tyr Leu

1 5

<210> SEQ ID NO: 266

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 266

Pro Phe Lys Pro Pro Pro Lys Pro Lys Pro

1 5 10

<210> SEQ ID NO: 267

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 267

Pro Lys Pro Lys Pro Pro Pro Lys Phe Pro

1 5 10

<210> SEQ ID NO: 268

<211> LENGTH: 9

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 268

Leu Tyr Pro Pro Lys Pro Ile Lys Lys

1 5

<210> SEQ ID NO: 269

<211> LENGTH: 9

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 269

Lys Lys Phe Pro Lys Pro Pro Phe Phe

1 5

<210> SEQ ID NO: 270

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 270

Glu Phe Glu Phe Phe Phe Arg Phe Phe Phe Gly Gly Gly Glu Phe Glu

1 5 10 15

Phe Phe Phe Arg Phe Phe Phe

20

<210> SEQ ID NO: 271

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 271

Gln Phe Glu Phe Phe Phe Arg Phe Phe Phe Gly Gly Gly Gln Phe Glu

1 5 10 15

Phe Phe Phe Arg Phe Phe Phe

20

<210> SEQ ID NO: 272

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 272

Asp Phe Glu Phe Phe Phe Arg Phe Phe Phe Gly Gly Gly Asp Phe Glu

1 5 10 15

Phe Phe Phe Arg Phe Phe Phe

20

<210> SEQ ID NO: 273

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 273

Glu Phe Asn Phe Phe Phe Arg Phe Phe Phe Gly Gly Gly Glu Phe Asn

1 5 10 15

Phe Phe Phe Arg Phe Phe Phe

20

<210> SEQ ID NO: 274

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 274

Phe Phe Phe Arg Phe Phe Phe Glu Phe Gln Phe Phe Phe Arg Phe Phe

1 5 10 15

Phe Glu Phe Gln

20

<210> SEQ ID NO: 275

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 275

Phe Phe Phe Arg Phe Phe Phe Glu Phe Gln Gly Gly Gly Phe Phe Phe

1 5 10 15

Arg Phe Phe Phe Glu Phe Gln

20

<210> SEQ ID NO: 276

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 276

Arg Trp Arg Lys Phe Phe Lys Arg Phe Phe Gln Phe Glu Phe Phe Phe

1 5 10 15

Arg Phe Phe Phe

20

<210> SEQ ID NO: 277

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 277

Arg Trp Arg Lys Phe Phe Lys Arg Phe Phe Gly Gly Gly Phe Phe Phe

1 5 10 15

Arg Phe Phe Phe Asn Phe Asn

20

<210> SEQ ID NO: 278

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 278

Arg Phe Arg Lys Phe Phe Lys Arg Phe Phe Gln Phe Glu Phe Phe Phe

1 5 10 15

Arg Phe Phe Phe

20

<210> SEQ ID NO: 279

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 279

Arg Phe Arg Lys Phe Phe Lys Arg Phe Phe Gly Gly Gly Phe Phe Phe

1 5 10 15

Arg Phe Phe Phe Asn Phe Asn

20

<210> SEQ ID NO: 280

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 280

Arg Trp Arg Lys Phe Phe Lys Arg Phe Phe Gly Gly Gly Phe Phe Phe

1 5 10 15

Arg Phe Phe Phe Glu Phe Gln

20

<210> SEQ ID NO: 281

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 281

Arg Phe Arg Lys Phe Phe Lys Arg Phe Phe Gly Gly Gly Phe Phe Phe

1 5 10 15

Arg Phe Phe Phe Glu Phe Gln

20

<210> SEQ ID NO: 282

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 282

Glu Phe Glu Phe Phe Phe Arg Phe Phe Phe Glu Phe Glu Phe Phe Phe

1 5 10 15

Arg Phe Phe Phe

20

<210> SEQ ID NO: 283

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 283

Arg Trp Arg Lys Phe Phe Lys Arg Phe Phe Asn Phe Asn Phe Phe Phe

1 5 10 15

Arg Phe Phe Phe

20

<210> SEQ ID NO: 284

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 284

Gln Phe Glu Phe Phe Phe Arg Phe Phe Phe Gln Phe Glu Phe Phe Phe

1 5 10 15

Arg Phe Phe Phe

20

<210> SEQ ID NO: 285

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 285

Arg Trp Arg Lys Phe Phe Lys Arg Phe Phe Gly Gly Gly Asn Phe Asn

1 5 10 15

Phe Phe Phe Arg Phe Phe Phe

20

<210> SEQ ID NO: 286

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 286

Glu Phe Asn Phe Phe Phe Arg Phe Phe Phe Glu Phe Asn Phe Phe Phe

1 5 10 15

Arg Phe Phe Phe

20

<210> SEQ ID NO: 287

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 287

Arg Phe Arg Lys Phe Phe Lys Arg Phe Phe Asn Phe Asn Phe Phe Phe

1 5 10 15

Arg Phe Phe Phe

20

<210> SEQ ID NO: 288

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 288

Phe Phe Arg Lys Phe Phe Lys Arg Phe Arg Gly Gly Gly Asn Phe Asn

1 5 10 15

Phe Phe Phe Arg Phe Phe Phe

20

<210> SEQ ID NO: 289

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 289

Arg Phe Arg Lys Phe Phe Lys Arg Phe Phe Gly Gly Gly Asn Phe Asn

1 5 10 15

Phe Phe Phe Arg Phe Phe Phe

20

<210> SEQ ID NO: 290

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 290

Asp Phe Glu Phe Phe Phe Arg Phe Phe Phe Asp Phe Glu Phe Phe Phe

1 5 10 15

Arg Phe Phe Phe

20

<210> SEQ ID NO: 291

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 291

Arg Trp Arg Lys Phe Phe Lys Arg Phe Phe Phe Phe Phe Arg Phe Phe

1 5 10 15

Phe Glu Phe Gln

20

<210> SEQ ID NO: 292

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 292

Arg Phe Arg Lys Phe Phe Lys Arg Phe Phe Phe Phe Phe Arg Phe Phe

1 5 10 15

Phe Glu Phe Gln

20

<210> SEQ ID NO: 293

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 293

Phe Phe Arg Lys Phe Phe Lys Arg Phe Arg Gly Gly Gly Phe Phe Phe

1 5 10 15

Arg Phe Phe Phe Asn Phe Asn

20

<210> SEQ ID NO: 294

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 294

Phe Phe Arg Lys Phe Phe Lys Arg Trp Arg Gly Gly Gly Phe Phe Phe

1 5 10 15

Arg Phe Phe Phe Asn Phe Asn

20

<210> SEQ ID NO: 295

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 295

Arg Phe Arg Lys Phe Phe Lys Arg Phe Phe Phe Phe Phe Arg Phe Phe

1 5 10 15

Phe Asn Phe Asn

20

<210> SEQ ID NO: 296

<211> LENGTH: 21

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 296

Phe Phe Arg Lys Phe Phe Lys Arg Phe Arg Phe Phe Phe Arg Phe Phe

1 5 10 15

Phe Glu Phe Gln Arg

20

<210> SEQ ID NO: 297

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 297

Phe Phe Glu His Phe Trp Lys Glu Phe Asn Gly Gly Gly Asn Phe Gln

1 5 10 15

Lys Trp Phe His Gln Phe Phe

20

<210> SEQ ID NO: 298

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 298

Phe Phe Arg Lys Phe Phe Lys Arg Trp Arg Gln Phe Glu Phe Phe Phe

1 5 10 15

Arg Phe Phe Phe

20

<210> SEQ ID NO: 299

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 299

Arg Trp Arg Lys Phe Phe Lys Arg Phe Phe Phe Phe Phe Arg Phe Phe

1 5 10 15

Phe Asn Phe Asn

20

<210> SEQ ID NO: 300

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 300

Asn Phe Gln Lys Trp Phe His Gln Phe Phe Gly Gly Gly Phe Phe Glu

1 5 10 15

His Phe Trp Lys Glu Phe Asn

20

<210> SEQ ID NO: 301

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 301

Phe Phe Arg Lys Phe Phe Lys Arg Trp Arg Gly Gly Gly Asn Phe Asn

1 5 10 15

Phe Phe Phe Arg Phe Phe Phe

20

<210> SEQ ID NO: 302

<211> LENGTH: 21

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 302

Phe Phe Arg Lys Phe Phe Lys Arg Trp Arg Phe Phe Phe Arg Phe Phe

1 5 10 15

Phe Glu Phe Gln Arg

20

<210> SEQ ID NO: 303

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 303

Phe Phe Arg Lys Phe Phe Lys Arg Trp Arg Asn Phe Asn Phe Phe Phe

1 5 10 15

Arg Phe Phe Phe

20

<210> SEQ ID NO: 304

<211> LENGTH: 24

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 304

Phe Phe Arg Lys Phe Phe Lys Arg Phe Arg Gly Gly Gly Phe Phe Phe

1 5 10 15

Arg Phe Phe Phe Glu Phe Gln Arg

20

<210> SEQ ID NO: 305

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 305

Phe Phe Arg Lys Phe Phe Lys Arg Phe Arg Gln Phe Glu Phe Phe Phe

1 5 10 15

Arg Phe Phe Phe

20

<210> SEQ ID NO: 306

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 306

Phe Phe Arg Lys Phe Phe Lys Arg Phe Arg Asn Phe Asn Phe Phe Phe

1 5 10 15

Arg Phe Phe Phe

20

<210> SEQ ID NO: 307

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 307

Arg Phe Arg Lys Phe Phe Lys Arg Phe Phe Gly Gly Gly Gln Phe Glu

1 5 10 15

Phe Phe Phe Arg Phe Phe Phe

20

<210> SEQ ID NO: 308

<211> LENGTH: 24

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 308

Phe Phe Arg Lys Phe Phe Lys Arg Trp Arg Gly Gly Gly Phe Phe Phe

1 5 10 15

Arg Phe Phe Phe Glu Phe Gln Arg

20

<210> SEQ ID NO: 309

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 309

Phe Phe Arg Lys Phe Phe Lys Arg Phe Arg Gly Gly Gly Gln Phe Glu

1 5 10 15

Phe Phe Phe Arg Phe Phe Phe

20

<210> SEQ ID NO: 310

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 310

Phe Phe Arg Lys Phe Phe Lys Arg Trp Arg Gly Gly Gly Gln Phe Glu

1 5 10 15

Phe Phe Phe Arg Phe Phe Phe

20

<210> SEQ ID NO: 311

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 311

Arg Trp Arg Lys Phe Phe Lys Arg Phe Phe Gly Gly Gly Gln Phe Glu

1 5 10 15

Phe Phe Phe Arg Phe Phe Phe

20

<210> SEQ ID NO: 312

<211> LENGTH: 22

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 312

Gln Phe Asn His Phe Phe Lys Glu Phe Gly Gly Gly Gln Phe Asn His

1 5 10 15

Phe Phe Lys Glu Phe Phe

20

<210> SEQ ID NO: 313

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 313

Phe Phe Arg Lys Phe Phe Lys Arg Phe Arg Phe Phe Phe Arg Phe Phe

1 5 10 15

Phe Asn Phe Asn

20

<210> SEQ ID NO: 314

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 314

Phe Phe Arg Lys Phe Phe Lys Arg Trp Arg Phe Phe Phe Arg Phe Phe

1 5 10 15

Phe Asn Phe Asn

20

<210> SEQ ID NO: 315

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 315

Phe Phe Glu His Phe Trp Lys Glu Phe Asn Gly Gly Gly Phe Phe Glu

1 5 10 15

His Phe Trp Lys Glu Phe Asn

20

<210> SEQ ID NO: 316

<211> LENGTH: 22

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 316

Phe Phe Glu His Phe Trp Lys Glu Phe Gly Gly Gly Asn Phe Gln Lys

1 5 10 15

Trp Phe His Gln Phe Phe

20

<210> SEQ ID NO: 317

<211> LENGTH: 22

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 317

Asn Phe Gln Lys Trp Phe His Gln Phe Gly Gly Gly Phe Phe Glu His

1 5 10 15

Phe Trp Lys Glu Phe Asn

20

<210> SEQ ID NO: 318

<211> LENGTH: 22

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 318

Phe Phe Glu His Phe Trp Lys Glu Phe Asn Gly Gly Gly Leu His Lys

1 5 10 15

Met Tyr Asn Gln Val Trp

20

<210> SEQ ID NO: 319

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 319

Asn Phe Gln Lys Trp Phe His Gln Phe Phe Gly Gly Gly Asn Phe Gln

1 5 10 15

Lys Trp Phe His Gln Phe Phe

20

<210> SEQ ID NO: 320

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 320

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Gly Gly Gly Asn Phe Gln

1 5 10 15

Lys Trp Phe His Gln Phe Phe

20

<210> SEQ ID NO: 321

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 321

Phe Phe Glu Lys Phe Phe His Asn Phe Gln Gly Gly Gly Phe Phe Glu

1 5 10 15

Lys Phe Phe His Asn Phe Gln

20

<210> SEQ ID NO: 322

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 322

Phe Phe Gln His Phe Trp Lys Gln Phe Asn Gly Gly Gly Phe Phe Gln

1 5 10 15

His Phe Trp Lys Gln Phe Asn

20

<210> SEQ ID NO: 323

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 323

Asn Phe Gln Lys Trp Phe His Gln Phe Phe Asn Phe Gln Lys Trp Phe

1 5 10 15

His Gln Phe Phe

20

<210> SEQ ID NO: 324

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 324

Phe Ala Lys Lys Phe Ala Gln Lys Phe Lys Gly Gly Gly Asn Phe Gln

1 5 10 15

Lys Trp Phe His Gln Phe Phe

20

<210> SEQ ID NO: 325

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 325

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Gly Gly Gly Gln Phe Glu

1 5 10 15

Phe Phe Phe Arg Phe Phe Phe

20

<210> SEQ ID NO: 326

<211> LENGTH: 19

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 326

Gln Phe Asn His Phe Phe Lys Glu Phe Gln Phe Asn His Phe Phe Lys

1 5 10 15

Glu Phe Phe

<210> SEQ ID NO: 327

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 327

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Gly Gly Gly Asp Phe Glu

1 5 10 15

Phe Phe Phe Arg Phe Phe Phe

20

<210> SEQ ID NO: 328

<211> LENGTH: 22

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 328

Phe Phe Glu His Phe Trp Lys Glu Phe Asn Gly Gly Gly Trp Val Gln

1 5 10 15

Asn Tyr Met Lys His Leu

20

<210> SEQ ID NO: 329

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 329

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Gln Phe Glu Phe Phe Phe

1 5 10 15

Arg Phe Phe Phe

20

<210> SEQ ID NO: 330

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 330

Phe Phe Gln His Phe Trp Lys Gln Phe Asn Phe Phe Gln His Phe Trp

1 5 10 15

Lys Gln Phe Asn

20

<210> SEQ ID NO: 331

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 331

Phe Phe Glu His Phe Trp Lys Glu Phe Asn Phe Phe Glu His Phe Trp

1 5 10 15

Lys Glu Phe Asn

20

<210> SEQ ID NO: 332

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 332

Asn Phe Glu Lys Trp Phe His Glu Phe Phe Asn Phe Glu Lys Trp Phe

1 5 10 15

His Glu Phe Phe

20

<210> SEQ ID NO: 333

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 333

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Gly Gly Gly Gln Phe Asn

1 5 10 15

His Phe Phe Lys Glu Phe Phe

20

<210> SEQ ID NO: 334

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 334

Asn Phe Glu Lys Trp Phe His Glu Phe Phe Gly Gly Gly Asn Phe Glu

1 5 10 15

Lys Trp Phe His Glu Phe Phe

20

<210> SEQ ID NO: 335

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 335

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Gly Gly Gly Phe Phe Phe

1 5 10 15

Arg Phe Phe Phe Glu Phe Gln

20

<210> SEQ ID NO: 336

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 336

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Asp Phe Glu Phe Phe Phe

1 5 10 15

Arg Phe Phe Phe

20

<210> SEQ ID NO: 337

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 337

Gln Phe Asn His Phe Phe Lys Glu Phe Phe Gly Gly Gly Gln Phe Asn

1 5 10 15

His Phe Phe Lys Glu Phe Phe

20

<210> SEQ ID NO: 338

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 338

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Gly Gly Gly Glu Phe Glu

1 5 10 15

Phe Phe Phe Arg Phe Phe Phe

20

<210> SEQ ID NO: 339

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 339

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Gly Gly Gly Glu Phe Asn

1 5 10 15

Phe Phe Phe Arg Phe Phe Phe

20

<210> SEQ ID NO: 340

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 340

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Gly Gly Gly Asn Phe Glu

1 5 10 15

Lys Trp Phe His Glu Phe Phe

20

<210> SEQ ID NO: 341

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 341

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Gly Gly Gly Phe Phe Glu

1 5 10 15

Lys Phe Phe His Asn Phe Gln

20

<210> SEQ ID NO: 342

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 342

Gln Phe Asn His Phe Phe Lys Glu Phe Phe Gln Phe Asn His Phe Phe

1 5 10 15

Lys Glu Phe Phe

20

<210> SEQ ID NO: 343

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 343

Phe Phe Glu Lys Phe Phe His Asn Phe Gln Phe Phe Glu Lys Phe Phe

1 5 10 15

His Asn Phe Gln

20

<210> SEQ ID NO: 344

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 344

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Glu Phe Glu Phe Phe Phe

1 5 10 15

Arg Phe Phe Phe

20

<210> SEQ ID NO: 345

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 345

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Glu Phe Asn Phe Phe Phe

1 5 10 15

Arg Phe Phe Phe

20

<210> SEQ ID NO: 346

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 346

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Phe Phe Glu His Phe Trp

1 5 10 15

Lys Glu Phe Asn

20

<210> SEQ ID NO: 347

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 347

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Phe Phe Phe Arg Phe Phe

1 5 10 15

Phe Glu Phe Gln

20

<210> SEQ ID NO: 348

<211> LENGTH: 19

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 348

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Leu His Lys Met Tyr Asn

1 5 10 15

Gln Val Trp

<210> SEQ ID NO: 349

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 349

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Gly Gly Gly Phe Phe Glu

1 5 10 15

His Phe Trp Lys Glu Phe Asn

20

<210> SEQ ID NO: 350

<211> LENGTH: 22

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 350

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Gly Gly Gly Trp Val Gln

1 5 10 15

Asn Tyr Met Lys His Leu

20

<210> SEQ ID NO: 351

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 351

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Asn Phe Gln Lys Trp Phe

1 5 10 15

His Gln Phe Phe

20

<210> SEQ ID NO: 352

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 352

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Phe Phe Gln His Phe Trp

1 5 10 15

Lys Gln Phe Asn

20

<210> SEQ ID NO: 353

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 353

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Gly Gly Gly Phe Phe Gln

1 5 10 15

His Phe Trp Lys Gln Phe Asn

20

<210> SEQ ID NO: 354

<211> LENGTH: 19

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 354

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Trp Val Gln Asn Tyr Met

1 5 10 15

Lys His Leu

<210> SEQ ID NO: 355

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 355

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Gln Phe Asn His Phe Phe

1 5 10 15

Lys Glu Phe Phe

20

<210> SEQ ID NO: 356

<211> LENGTH: 22

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 356

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Gly Gly Gly Leu His Lys

1 5 10 15

Met Tyr Asn Gln Val Trp

20

<210> SEQ ID NO: 357

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 357

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Asn Phe Glu Lys Trp Phe

1 5 10 15

His Glu Phe Phe

20

<210> SEQ ID NO: 358

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 358

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Phe Phe Glu Lys Phe Phe

1 5 10 15

His Asn Phe Gln

20

<210> SEQ ID NO: 359

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 359

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Gly Gly Gly Ala Phe Phe

1 5 10 15

Lys Lys Lys Ala Lys Phe Lys

20

<210> SEQ ID NO: 360

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 360

Ala Phe Phe Lys Lys Lys Ala Lys Phe Lys Gly Gly Gly Ala Phe Phe

1 5 10 15

Lys Lys Lys Ala Lys Phe Lys

20

<210> SEQ ID NO: 361

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 361

Lys Phe Lys Lys Ala Phe Lys Lys Ala Phe Lys Phe Lys Lys Ala Phe

1 5 10 15

Lys Lys Ala Phe

20

<210> SEQ ID NO: 362

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 362

Lys Phe Lys Lys Ala Phe Lys Lys Ala Phe Gly Gly Gly Lys Phe Lys

1 5 10 15

Lys Ala Phe Lys Lys Ala Phe

20

<210> SEQ ID NO: 363

<211> LENGTH: 23

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 363

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Gly Gly Gly Phe Ala Lys

1 5 10 15

Lys Phe Ala Lys Lys Phe Lys

20

<210> SEQ ID NO: 364

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 364

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Ala Phe Phe Lys Lys Lys

1 5 10 15

Ala Lys Phe Lys

20

<210> SEQ ID NO: 365

<211> LENGTH: 22

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 365

Pro Ser Arg Lys Ser Met Glu Lys Ser Val Ala Lys Leu Leu Asn Lys

1 5 10 15

Ile Ala Lys Ser Glu Pro

20

<210> SEQ ID NO: 366

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 366

Ala Phe Phe Lys Lys Lys Ala Lys Phe Lys Ala Phe Phe Lys Lys Lys

1 5 10 15

Ala Lys Phe Lys

20

<210> SEQ ID NO: 367

<211> LENGTH: 579

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 367

Met Leu Arg Ser Gly Pro Ala Ser Gly Pro Ser Val Pro Thr Gly Arg

1 5 10 15

Ala Met Pro Ser Arg Arg Val Ala Arg Pro Pro Ala Ala Pro Glu Leu

20 25 30

Gly Ala Leu Gly Ser Pro Asp Leu Ser Ser Leu Ser Leu Ala Val Ser

35 40 45

Arg Ser Thr Asp Glu Leu Glu Ile Ile Asp Glu Tyr Ile Lys Glu Asn

50 55 60

Gly Phe Gly Leu Asp Gly Gly Gln Pro Gly Pro Gly Glu Gly Leu Pro

65 70 75 80

Arg Leu Val Ser Arg Gly Ala Ala Ser Leu Ser Thr Val Thr Leu Gly

85 90 95

Pro Val Ala Pro Pro Ala Thr Pro Pro Pro Trp Gly Cys Pro Leu Gly

100 105 110

Arg Leu Val Ser Pro Ala Pro Gly Pro Gly Pro Gln Pro His Leu Val

115 120 125

Ile Thr Glu Gln Pro Lys Gln Arg Gly Met Arg Phe Arg Tyr Glu Cys

130 135 140

Glu Gly Arg Ser Ala Gly Ser Ile Leu Gly Glu Ser Ser Thr Glu Ala

145 150 155 160

Ser Lys Thr Leu Pro Ala Ile Glu Leu Arg Asp Cys Gly Gly Leu Arg

165 170 175

Glu Val Glu Val Thr Ala Cys Leu Val Trp Lys Asp Trp Pro His Arg

180 185 190

Val His Pro His Ser Leu Val Gly Lys Asp Cys Thr Asp Gly Ile Cys

195 200 205

Arg Val Arg Leu Arg Pro His Val Ser Pro Arg His Ser Phe Asn Asn

210 215 220

Leu Gly Ile Gln Cys Val Arg Lys Lys Glu Ile Glu Ala Ala Ile Glu

225 230 235 240

Arg Lys Ile Gln Leu Gly Ile Asp Pro Tyr Asn Ala Gly Ser Leu Lys

245 250 255

Asn His Gln Glu Val Asp Met Asn Val Val Arg Ile Cys Phe Gln Ala

260 265 270

Ser Tyr Arg Asp Gln Gln Gly Gln Met Arg Arg Met Asp Pro Val Leu

275 280 285

Ser Glu Pro Val Tyr Asp Lys Lys Ser Thr Asn Thr Ser Glu Leu Arg

290 295 300

Ile Cys Arg Ile Asn Lys Glu Ser Gly Pro Cys Thr Gly Gly Glu Glu

305 310 315 320

Leu Tyr Leu Leu Cys Asp Lys Val Gln Lys Glu Asp Ile Ser Val Val

325 330 335

Phe Ser Arg Ala Ser Trp Glu Gly Arg Ala Asp Phe Ser Gln Ala Asp

340 345 350

Val His Arg Gln Ile Ala Ile Val Phe Lys Thr Pro Pro Tyr Glu Asp

355 360 365

Leu Glu Ile Val Glu Pro Val Thr Val Asn Val Phe Leu Gln Arg Leu

370 375 380

Thr Asp Gly Val Cys Ser Glu Pro Leu Pro Phe Thr Tyr Leu Pro Arg

385 390 395 400

Asp His Asp Ser Tyr Gly Val Asp Lys Lys Arg Lys Arg Gly Met Pro

405 410 415

Asp Val Leu Gly Glu Leu Asn Ser Ser Asp Pro His Gly Ile Glu Ser

420 425 430

Lys Arg Arg Lys Lys Lys Pro Ala Ile Leu Asp His Phe Leu Pro Asn

435 440 445

His Gly Ser Gly Pro Phe Leu Pro Pro Ser Ala Leu Leu Pro Asp Pro

450 455 460

Asp Phe Phe Ser Gly Thr Val Ser Leu Pro Gly Leu Glu Pro Pro Gly

465 470 475 480

Gly Pro Asp Leu Leu Asp Asp Gly Phe Ala Tyr Asp Pro Thr Ala Pro

485 490 495

Thr Leu Phe Thr Met Leu Asp Leu Leu Pro Pro Ala Pro Pro His Ala

500 505 510

Ser Ala Val Val Cys Ser Gly Gly Ala Gly Ala Val Val Gly Glu Thr

515 520 525

Pro Gly Pro Glu Pro Leu Thr Leu Asp Ser Tyr Gln Ala Pro Gly Pro

530 535 540

Gly Asp Gly Gly Thr Ala Ser Leu Val Gly Ser Asn Met Phe Pro Asn

545 550 555 560

His Tyr Arg Glu Ala Ala Phe Gly Gly Gly Leu Leu Ser Pro Gly Pro

565 570 575

Glu Ala Thr

<210> SEQ ID NO: 368

<211> LENGTH: 390

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 368

Met Pro Pro Ser Gly Leu Arg Leu Leu Pro Leu Leu Leu Pro Leu Leu

1 5 10 15

Trp Leu Leu Val Leu Thr Pro Gly Arg Pro Ala Ala Gly Leu Ser Thr

20 25 30

Cys Lys Thr Ile Asp Met Glu Leu Val Lys Arg Lys Arg Ile Glu Ala

35 40 45

Ile Arg Gly Gln Ile Leu Ser Lys Leu Arg Leu Ala Ser Pro Pro Ser

50 55 60

Gln Gly Glu Val Pro Pro Gly Pro Leu Pro Glu Ala Val Leu Ala Leu

65 70 75 80

Tyr Asn Ser Thr Arg Asp Arg Val Ala Gly Glu Ser Ala Glu Pro Glu

85 90 95

Pro Glu Pro Glu Ala Asp Tyr Tyr Ala Lys Glu Val Thr Arg Val Leu

100 105 110

Met Val Glu Thr His Asn Glu Ile Tyr Asp Lys Phe Lys Gln Ser Thr

115 120 125

His Ser Ile Tyr Met Phe Phe Asn Thr Ser Glu Leu Arg Glu Ala Val

130 135 140

Pro Glu Pro Val Leu Leu Ser Arg Ala Glu Leu Arg Leu Leu Arg Leu

145 150 155 160

Lys Leu Lys Val Glu Gln His Val Glu Leu Tyr Gln Lys Tyr Ser Asn

165 170 175

Asn Ser Trp Arg Tyr Leu Ser Asn Arg Leu Leu Ala Pro Ser Asp Ser

180 185 190

Pro Glu Trp Leu Ser Phe Asp Val Thr Gly Val Val Arg Gln Trp Leu

195 200 205

Ser Arg Gly Gly Glu Ile Glu Gly Phe Arg Leu Ser Ala His Cys Ser

210 215 220

Cys Asp Ser Arg Asp Asn Thr Leu Gln Val Asp Ile Asn Gly Phe Thr

225 230 235 240

Thr Gly Arg Arg Gly Asp Leu Ala Thr Ile His Gly Met Asn Arg Pro

245 250 255

Phe Leu Leu Leu Met Ala Thr Pro Leu Glu Arg Ala Gln His Leu Gln

260 265 270

Ser Ser Arg His Arg Arg Ala Leu Asp Thr Asn Tyr Cys Phe Ser Ser

275 280 285

Thr Glu Lys Asn Cys Cys Val Arg Gln Leu Tyr Ile Asp Phe Arg Lys

290 295 300

Asp Leu Gly Trp Lys Trp Ile His Glu Pro Lys Gly Tyr His Ala Asn

305 310 315 320

Phe Cys Leu Gly Pro Cys Pro Tyr Ile Trp Ser Leu Asp Thr Gln Tyr

325 330 335

Ser Lys Val Leu Ala Leu Tyr Asn Gln His Asn Pro Gly Ala Ser Ala

340 345 350

Ala Pro Cys Cys Val Pro Gln Ala Leu Glu Pro Leu Pro Ile Val Tyr

355 360 365

Tyr Val Gly Arg Lys Pro Lys Val Glu Gln Leu Ser Asn Met Ile Val

370 375 380

Arg Ser Cys Lys Cys Ser

385 390

<210> SEQ ID NO: 369

<211> LENGTH: 2556

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: MISC_FEATURE

<222> LOCATION: (891)..(891)

<223> OTHER INFORMATION: Xaa is denoted “X” in GenBank Sequence for Homo

sapiens Notch1 (GenBank Acc. No. AAG33848.1)

<400> SEQENCE: 369

Met Pro Pro Leu Leu Ala Pro Leu Leu Cys Leu Ala Leu Leu Pro Ala

1 5 10 15

Leu Ala Ala Arg Gly Pro Arg Cys Ser Gln Pro Gly Glu Thr Cys Leu

20 25 30

Asn Gly Gly Lys Cys Glu Ala Ala Asn Gly Thr Glu Ala Cys Val Cys

35 40 45

Gly Gly Ala Phe Val Gly Pro Arg Cys Gln Asp Pro Asn Pro Cys Leu

50 55 60

Ser Thr Pro Cys Lys Asn Ala Gly Thr Cys His Val Val Asp Arg Arg

65 70 75 80

Gly Val Ala Asp Tyr Ala Cys Ser Cys Ala Leu Gly Phe Ser Gly Pro

85 90 95

Leu Cys Leu Thr Pro Leu Asp Asn Ala Cys Leu Thr Asn Pro Cys Arg

100 105 110

Asn Gly Gly Thr Cys Asp Leu Leu Thr Leu Thr Glu Tyr Lys Cys Arg

115 120 125

Cys Pro Pro Gly Trp Ser Gly Lys Ser Cys Gln Gln Ala Asp Pro Cys

130 135 140

Ala Ser Asn Pro Cys Ala Asn Gly Gly Gln Cys Leu Pro Phe Glu Ala

145 150 155 160

Ser Tyr Ile Cys His Cys Pro Pro Ser Phe His Gly Pro Thr Cys Arg

165 170 175

Gln Asp Val Asn Glu Cys Gly Gln Lys Pro Arg Leu Cys Arg His Gly

180 185 190

Gly Thr Cys His Asn Glu Val Gly Ser Tyr Arg Cys Val Cys Arg Ala

195 200 205

Thr His Thr Gly Pro Asn Cys Glu Arg Pro Tyr Val Pro Cys Ser Pro

210 215 220

Ser Pro Cys Gln Asn Gly Gly Thr Cys Arg Pro Thr Gly Asp Val Thr

225 230 235 240

His Glu Cys Ala Cys Leu Pro Gly Phe Thr Gly Gln Asn Cys Glu Glu

245 250 255

Asn Ile Asp Asp Cys Pro Gly Asn Asn Cys Lys Asn Gly Gly Ala Cys

260 265 270

Val Asp Gly Val Asn Thr Tyr Asn Cys Pro Cys Pro Pro Glu Trp Thr

275 280 285

Gly Gln Tyr Cys Thr Glu Asp Val Asp Glu Cys Gln Leu Met Pro Asn

290 295 300

Ala Cys Gln Asn Gly Gly Thr Cys His Asn Thr His Gly Gly Tyr Asn

305 310 315 320

Cys Val Cys Val Asn Gly Trp Thr Gly Glu Asp Cys Ser Glu Asn Ile

325 330 335

Asp Asp Cys Ala Ser Ala Ala Cys Phe His Gly Ala Thr Cys His Asp

340 345 350

Arg Val Ala Ser Phe Tyr Cys Glu Cys Pro His Gly Arg Thr Gly Leu

355 360 365

Leu Cys His Leu Asn Asp Ala Cys Ile Ser Asn Pro Cys Asn Glu Gly

370 375 380

Ser Asn Cys Asp Thr Asn Pro Val Asn Gly Lys Ala Ile Cys Thr Cys

385 390 395 400

Pro Ser Gly Tyr Thr Gly Pro Ala Cys Ser Gln Asp Val Asp Glu Cys

405 410 415

Ser Leu Gly Ala Asn Pro Cys Glu His Ala Gly Lys Cys Ile Asn Thr

420 425 430

Leu Gly Ser Phe Glu Cys Gln Cys Leu Gln Gly Tyr Thr Gly Pro Arg

435 440 445

Cys Glu Ile Asp Val Asn Glu Cys Val Ser Asn Pro Cys Gln Asn Asp

450 455 460

Ala Thr Cys Leu Asp Gln Ile Gly Glu Phe Gln Cys Met Cys Met Pro

465 470 475 480

Gly Tyr Glu Gly Val His Cys Glu Val Asn Thr Asp Glu Cys Ala Ser

485 490 495

Ser Pro Cys Leu His Asn Gly Arg Cys Leu Asp Lys Ile Asn Glu Phe

500 505 510

Gln Cys Glu Cys Pro Thr Gly Phe Thr Gly His Leu Cys Gln Tyr Asp

515 520 525

Val Asp Glu Cys Ala Ser Thr Pro Cys Lys Asn Gly Ala Lys Cys Leu

530 535 540

Asp Gly Pro Asn Thr Tyr Thr Cys Val Cys Thr Glu Gly Tyr Thr Gly

545 550 555 560

Thr His Cys Glu Val Asp Ile Asp Glu Cys Asp Pro Asp Pro Cys His

565 570 575

Tyr Gly Ser Cys Lys Asp Gly Val Ala Thr Phe Thr Cys Leu Cys Arg

580 585 590

Pro Gly Tyr Thr Gly His His Cys Glu Thr Asn Ile Asn Glu Cys Ser

595 600 605

Ser Gln Pro Cys Arg Leu Arg Gly Thr Cys Gln Asp Pro Asp Asn Ala

610 615 620

Tyr Leu Cys Phe Cys Leu Lys Gly Thr Thr Gly Pro Asn Cys Glu Ile

625 630 635 640

Asn Leu Asp Asp Cys Ala Ser Ser Pro Cys Asp Ser Gly Thr Cys Leu

645 650 655

Asp Lys Ile Asp Gly Tyr Glu Cys Ala Cys Glu Pro Gly Tyr Thr Gly

660 665 670

Ser Met Cys Asn Ser Asn Ile Asp Glu Cys Ala Gly Asn Pro Cys His

675 680 685

Asn Gly Gly Thr Cys Glu Asp Gly Ile Asn Gly Phe Thr Cys Arg Cys

690 695 700

Pro Glu Gly Tyr His Asp Pro Thr Cys Leu Ser Glu Val Asn Glu Cys

705 710 715 720

Asn Ser Asn Pro Cys Val His Gly Ala Cys Arg Asp Ser Leu Asn Gly

725 730 735

Tyr Lys Cys Asp Cys Asp Pro Gly Trp Ser Gly Thr Asn Cys Asp Ile

740 745 750

Asn Asn Asn Glu Cys Glu Ser Asn Pro Cys Val Asn Gly Gly Thr Cys

755 760 765

Lys Asp Met Thr Ser Gly Ile Val Cys Thr Cys Arg Glu Gly Phe Ser

770 775 780

Gly Pro Asn Cys Gln Thr Asn Ile Asn Glu Cys Ala Ser Asn Pro Cys

785 790 795 800

Leu Asn Lys Gly Thr Cys Ile Asp Asp Val Ala Gly Tyr Lys Cys Asn

805 810 815

Cys Leu Leu Pro Tyr Thr Gly Ala Thr Cys Glu Val Val Leu Ala Pro

820 825 830

Cys Ala Pro Ser Pro Cys Arg Asn Gly Gly Glu Cys Arg Gln Ser Glu

835 840 845

Asp Tyr Glu Ser Phe Ser Cys Val Cys Pro Thr Ala Gly Ala Lys Gly

850 855 860

Gln Thr Cys Glu Val Asp Ile Asn Glu Cys Val Leu Ser Pro Cys Arg

865 870 875 880

His Gly Ala Ser Cys Gln Asn Thr His Gly Xaa Tyr Arg Cys His Cys

885 890 895

Gln Ala Gly Tyr Ser Gly Arg Asn Cys Glu Thr Asp Ile Asp Asp Cys

900 905 910

Arg Pro Asn Pro Cys His Asn Gly Gly Ser Cys Thr Asp Gly Ile Asn

915 920 925

Thr Ala Phe Cys Asp Cys Leu Pro Gly Phe Arg Gly Thr Phe Cys Glu

930 935 940

Glu Asp Ile Asn Glu Cys Ala Ser Asp Pro Cys Arg Asn Gly Ala Asn

945 950 955 960

Cys Thr Asp Cys Val Asp Ser Tyr Thr Cys Thr Cys Pro Ala Gly Phe

965 970 975

Ser Gly Ile His Cys Glu Asn Asn Thr Pro Asp Cys Thr Glu Ser Ser

980 985 990

Cys Phe Asn Gly Gly Thr Cys Val Asp Gly Ile Asn Ser Phe Thr Cys

995 1000 1005

Leu Cys Pro Pro Gly Phe Thr Gly Ser Tyr Cys Gln His Val Val

1010 1015 1020

Asn Glu Cys Asp Ser Arg Pro Cys Leu Leu Gly Gly Thr Cys Gln

1025 1030 1035

Asp Gly Arg Gly Leu His Arg Cys Thr Cys Pro Gln Gly Tyr Thr

1040 1045 1050

Gly Pro Asn Cys Gln Asn Leu Val His Trp Cys Asp Ser Ser Pro

1055 1060 1065

Cys Lys Asn Gly Gly Lys Cys Trp Gln Thr His Thr Gln Tyr Arg

1070 1075 1080

Cys Glu Cys Pro Ser Gly Trp Thr Gly Leu Tyr Cys Asp Val Pro

1085 1090 1095

Ser Val Ser Cys Glu Val Ala Ala Gln Arg Gln Gly Val Asp Val

1100 1105 1110

Ala Arg Leu Cys Gln His Gly Gly Leu Cys Val Asp Ala Gly Asn

1115 1120 1125

Thr His His Cys Arg Cys Gln Ala Gly Tyr Thr Gly Ser Tyr Cys

1130 1135 1140

Glu Asp Leu Val Asp Glu Cys Ser Pro Ser Pro Cys Gln Asn Gly

1145 1150 1155

Ala Thr Cys Thr Asp Tyr Leu Gly Gly Tyr Ser Cys Lys Cys Val

1160 1165 1170

Ala Gly Tyr His Gly Val Asn Cys Ser Glu Glu Ile Asp Glu Cys

1175 1180 1185

Leu Ser His Pro Cys Gln Asn Gly Gly Thr Cys Leu Asp Leu Pro

1190 1195 1200

Asn Thr Tyr Lys Cys Ser Cys Pro Arg Gly Thr Gln Gly Val His

1205 1210 1215

Cys Glu Ile Asn Val Asp Asp Cys Asn Pro Pro Val Asp Pro Val

1220 1225 1230

Ser Arg Ser Pro Lys Cys Phe Asn Asn Gly Thr Cys Val Asp Gln

1235 1240 1245

Val Gly Gly Tyr Ser Cys Thr Cys Pro Pro Gly Phe Val Gly Glu

1250 1255 1260

Arg Cys Glu Gly Asp Val Asn Glu Cys Leu Ser Asn Pro Cys Asp

1265 1270 1275

Ala Arg Gly Thr Gln Asn Cys Val Gln Arg Val Asn Asp Phe His

1280 1285 1290

Cys Glu Cys Arg Ala Gly His Thr Gly Arg Arg Cys Glu Ser Val

1295 1300 1305

Ile Asn Gly Cys Lys Gly Lys Pro Cys Lys Asn Gly Gly Thr Cys

1310 1315 1320

Ala Val Ala Ser Asn Thr Ala Arg Gly Phe Ile Cys Lys Cys Pro

1325 1330 1335

Ala Gly Phe Glu Gly Ala Thr Cys Glu Asn Asp Ala Arg Thr Cys

1340 1345 1350

Gly Ser Leu Arg Cys Leu Asn Gly Gly Thr Cys Ile Ser Gly Pro

1355 1360 1365

Arg Ser Pro Thr Cys Leu Cys Leu Gly Pro Phe Thr Gly Pro Glu

1370 1375 1380

Cys Gln Phe Pro Ala Ser Ser Pro Cys Leu Gly Gly Asn Pro Cys

1385 1390 1395

Tyr Asn Gln Gly Thr Cys Glu Pro Thr Ser Glu Ser Pro Phe Tyr

1400 1405 1410

Arg Cys Leu Cys Pro Ala Lys Phe Asn Gly Leu Leu Cys His Ile

1415 1420 1425

Leu Asp Tyr Ser Phe Gly Gly Gly Ala Gly Arg Asp Ile Pro Pro

1430 1435 1440

Pro Leu Ile Glu Glu Ala Cys Glu Leu Pro Glu Cys Gln Glu Asp

1445 1450 1455

Ala Gly Asn Lys Val Cys Ser Leu Gln Cys Asn Asn His Ala Cys

1460 1465 1470

Gly Trp Asp Gly Gly Asp Cys Ser Leu Asn Phe Asn Asp Pro Trp

1475 1480 1485

Lys Asn Cys Thr Gln Ser Leu Gln Cys Trp Lys Tyr Phe Ser Asp

1490 1495 1500

Gly His Cys Asp Ser Gln Cys Asn Ser Ala Gly Cys Leu Phe Asp

1505 1510 1515

Gly Phe Asp Cys Gln Arg Ala Glu Gly Gln Cys Asn Pro Leu Tyr

1520 1525 1530

Asp Gln Tyr Cys Lys Asp His Phe Ser Asp Gly His Cys Asp Gln

1535 1540 1545

Gly Cys Asn Ser Ala Glu Cys Glu Trp Asp Gly Leu Asp Cys Ala

1550 1555 1560

Glu His Val Pro Glu Arg Leu Ala Ala Gly Thr Leu Val Val Val

1565 1570 1575

Val Leu Met Pro Pro Glu Gln Leu Arg Asn Ser Ser Phe His Phe

1580 1585 1590

Leu Arg Glu Leu Ser Arg Val Leu His Thr Asn Val Val Phe Lys

1595 1600 1605

Arg Asp Ala His Gly Gln Gln Met Ile Phe Pro Tyr Tyr Gly Arg

1610 1615 1620

Glu Glu Glu Leu Arg Lys His Pro Ile Lys Arg Ala Ala Glu Gly

1625 1630 1635

Trp Ala Ala Pro Asp Ala Leu Leu Gly Gln Val Lys Ala Ser Leu

1640 1645 1650

Leu Pro Gly Gly Ser Glu Gly Gly Arg Arg Arg Arg Glu Leu Asp

1655 1660 1665

Pro Met Asp Val Arg Gly Ser Ile Val Tyr Leu Glu Ile Asp Asn

1670 1675 1680

Arg Gln Cys Val Gln Ala Ser Ser Gln Cys Phe Gln Ser Ala Thr

1685 1690 1695

Asp Val Ala Ala Phe Leu Gly Ala Leu Ala Ser Leu Gly Ser Leu

1700 1705 1710

Asn Ile Pro Tyr Lys Ile Glu Ala Val Gln Ser Glu Thr Val Glu

1715 1720 1725

Pro Pro Pro Pro Ala Gln Leu His Phe Met Tyr Val Ala Ala Ala

1730 1735 1740

Ala Phe Val Leu Leu Phe Phe Val Gly Cys Gly Val Leu Leu Ser

1745 1750 1755

Arg Lys Arg Arg Arg Gln His Gly Gln Leu Trp Phe Pro Glu Gly

1760 1765 1770

Phe Lys Val Ser Glu Ala Ser Lys Lys Lys Arg Arg Glu Pro Leu

1775 1780 1785

Gly Glu Asp Ser Val Gly Leu Lys Pro Leu Lys Asn Ala Ser Asp

1790 1795 1800

Gly Ala Leu Met Asp Asp Asn Gln Asn Glu Trp Gly Asp Glu Asp

1805 1810 1815

Leu Glu Thr Lys Lys Phe Arg Phe Glu Glu Pro Val Val Leu Pro

1820 1825 1830

Asp Leu Asp Asp Gln Thr Asp His Arg Gln Trp Thr Gln Gln His

1835 1840 1845

Leu Asp Ala Ala Asp Leu Arg Met Ser Ala Met Ala Pro Thr Pro

1850 1855 1860

Pro Gln Gly Glu Val Asp Ala Asp Cys Met Asp Val Asn Val Arg

1865 1870 1875

Gly Pro Asp Gly Phe Thr Pro Leu Met Ile Ala Ser Cys Ser Gly

1880 1885 1890

Gly Gly Leu Glu Thr Gly Asn Ser Glu Glu Glu Glu Asp Ala Pro

1895 1900 1905

Ala Val Ile Ser Asp Phe Ile Tyr Gln Gly Ala Ser Leu His Asn

1910 1915 1920

Gln Thr Asp Arg Thr Gly Glu Thr Ala Leu His Leu Ala Ala Arg

1925 1930 1935

Tyr Ser Arg Ser Asp Ala Ala Lys Arg Leu Leu Glu Ala Ser Ala

1940 1945 1950

Asp Ala Asn Ile Gln Asp Asn Met Gly Arg Thr Pro Leu His Ala

1955 1960 1965

Ala Val Ser Ala Asp Ala Gln Gly Val Phe Gln Ile Leu Ile Arg

1970 1975 1980

Asn Arg Ala Thr Asp Leu Asp Ala Arg Met His Asp Gly Thr Thr

1985 1990 1995

Pro Leu Ile Leu Ala Ala Arg Leu Ala Val Glu Gly Met Leu Glu

2000 2005 2010

Asp Leu Ile Asn Ser His Ala Asp Val Asn Ala Val Asp Asp Leu

2015 2020 2025

Gly Lys Ser Ala Leu His Trp Ala Ala Ala Val Asn Asn Val Asp

2030 2035 2040

Ala Ala Val Val Leu Leu Lys Asn Gly Ala Asn Lys Asp Met Gln

2045 2050 2055

Asn Asn Arg Glu Glu Thr Pro Leu Phe Leu Ala Ala Arg Glu Gly

2060 2065 2070

Ser Tyr Glu Thr Ala Lys Val Leu Leu Asp His Phe Ala Asn Arg

2075 2080 2085

Asp Ile Thr Asp His Met Asp Arg Leu Pro Arg Asp Ile Ala Gln

2090 2095 2100

Glu Arg Met His His Asp Ile Val Arg Leu Leu Asp Glu Tyr Asn

2105 2110 2115

Leu Val Arg Ser Pro Gln Leu His Gly Ala Pro Leu Gly Gly Thr

2120 2125 2130

Pro Thr Leu Ser Pro Pro Leu Cys Ser Pro Asn Gly Tyr Leu Gly

2135 2140 2145

Ser Leu Lys Pro Gly Val Gln Gly Lys Lys Val Arg Lys Pro Ser

2150 2155 2160

Ser Lys Gly Leu Ala Cys Gly Ser Lys Glu Ala Lys Asp Leu Lys

2165 2170 2175

Ala Arg Arg Lys Lys Ser Gln Asp Gly Lys Gly Cys Leu Leu Asp

2180 2185 2190

Ser Ser Gly Met Leu Ser Pro Val Asp Ser Leu Glu Ser Pro His

2195 2200 2205

Gly Tyr Leu Ser Asp Val Ala Ser Pro Pro Leu Leu Pro Ser Pro

2210 2215 2220

Phe Gln Gln Ser Pro Ser Val Pro Leu Asn His Leu Pro Gly Met

2225 2230 2235

Pro Asp Thr His Leu Gly Ile Gly His Leu Asn Val Ala Ala Lys

2240 2245 2250

Pro Glu Met Ala Ala Leu Gly Gly Gly Gly Arg Leu Ala Phe Glu

2255 2260 2265

Thr Gly Pro Pro Arg Leu Ser His Leu Pro Val Ala Ser Gly Thr

2270 2275 2280

Ser Thr Val Leu Gly Ser Ser Ser Gly Gly Ala Leu Asn Phe Thr

2285 2290 2295

Val Gly Gly Ser Thr Ser Leu Asn Gly Gln Cys Glu Trp Leu Ser

2300 2305 2310

Arg Leu Gln Ser Gly Met Val Pro Asn Gln Tyr Asn Pro Leu Arg

2315 2320 2325

Gly Ser Val Ala Pro Gly Pro Leu Ser Thr Gln Ala Pro Ser Leu

2330 2335 2340

Gln His Gly Met Val Gly Pro Leu His Ser Ser Leu Ala Ala Ser

2345 2350 2355

Ala Leu Ser Gln Met Met Ser Tyr Gln Gly Leu Pro Ser Thr Arg

2360 2365 2370

Leu Ala Thr Gln Pro His Leu Val Gln Thr Gln Gln Val Gln Pro

2375 2380 2385

Gln Asn Leu Gln Met Gln Gln Gln Asn Leu Gln Pro Ala Asn Ile

2390 2395 2400

Gln Gln Gln Gln Ser Leu Gln Pro Pro Pro Pro Pro Pro Gln Pro

2405 2410 2415

His Leu Gly Val Ser Ser Ala Ala Ser Gly His Leu Gly Arg Ser

2420 2425 2430

Phe Leu Ser Gly Glu Pro Ser Gln Ala Asp Val Gln Pro Leu Gly

2435 2440 2445

Pro Ser Ser Leu Ala Val His Thr Ile Leu Pro Gln Glu Ser Pro

2450 2455 2460

Ala Leu Pro Thr Ser Leu Pro Ser Ser Leu Val Pro Pro Val Thr

2465 2470 2475

Ala Ala Gln Phe Leu Thr Pro Pro Ser Gln His Ser Tyr Ser Ser

2480 2485 2490

Pro Val Asp Asn Thr Pro Ser His Gln Leu Gln Val Pro Glu His

2495 2500 2505

Pro Phe Leu Thr Pro Ser Pro Glu Ser Pro Asp Gln Trp Ser Ser

2510 2515 2520

Ser Ser Pro His Ser Asn Val Ser Asp Trp Ser Glu Gly Val Ser

2525 2530 2535

Ser Pro Pro Thr Ser Met Gln Ser Gln Ile Ala Arg Ile Pro Glu

2540 2545 2550

Ala Phe Lys

2555

<210> SEQ ID NO: 370

<211> LENGTH: 390

<212> TYPE: PRT

<213> ORGANISM: Bos taurus

<400> SEQENCE: 370

Met Glu Trp Gly Tyr Leu Leu Glu Val Thr Ser Leu Leu Ala Ala Leu

1 5 10 15

Ala Leu Leu Gln Arg Ser Ser Gly Ala Ala Ala Ala Ser Ala Lys Glu

20 25 30

Leu Ala Cys Gln Glu Ile Thr Val Pro Leu Cys Lys Gly Ile Gly Tyr

35 40 45

Asn Tyr Thr Tyr Met Pro Asn Gln Phe Asn His Asp Thr Gln Asp Glu

50 55 60

Ala Gly Leu Glu Val His Gln Phe Trp Pro Leu Val Glu Ile Gln Cys

65 70 75 80

Ser Pro Asp Leu Lys Phe Phe Leu Cys Ser Met Tyr Thr Pro Ile Cys

85 90 95

Leu Glu Asp Tyr Lys Lys Pro Leu Pro Pro Cys Arg Ser Val Cys Glu

100 105 110

Arg Ala Lys Ala Gly Cys Ala Pro Leu Met Arg Gln Tyr Gly Phe Ala

115 120 125

Trp Pro Asp Arg Met Arg Cys Asp Arg Leu Pro Glu Gln Gly Asn Pro

130 135 140

Asp Thr Leu Cys Met Asp Tyr Asn Arg Thr Asp Leu Thr Thr Ala Ala

145 150 155 160

Ser Ser Val Asp Gly Asp Pro Val Ala Gly Ile Cys Tyr Val Gly Asn

165 170 175

Gln Ser Leu Asp Asn Leu Leu Gly Phe Val Leu Ala Pro Leu Val Ile

180 185 190

Tyr Leu Phe Ile Gly Thr Met Phe Leu Leu Ala Gly Phe Val Ser Leu

195 200 205

Phe Arg Ile Arg Ser Val Ile Lys Gln Gln Gly Gly Pro Thr Lys Thr

210 215 220

His Lys Leu Glu Lys Leu Met Ile Arg Leu Gly Leu Phe Thr Val Leu

225 230 235 240

Tyr Thr Val Pro Ala Ala Val Val Val Ala Cys Leu Phe Tyr Glu Gln

245 250 255

His Asn Arg Pro Arg Trp Glu Ala Thr His Asn Cys Pro Cys Leu Arg

260 265 270

Asp Leu Gln Pro Asp Gln Ala Arg Arg Pro Asp Tyr Ala Val Phe Met

275 280 285

Leu Lys Tyr Phe Met Cys Leu Val Val Gly Ile Thr Ser Gly Val Trp

290 295 300

Val Trp Ser Gly Lys Thr Leu Glu Ser Trp Arg Ala Leu Cys Thr Arg

305 310 315 320

Cys Cys Trp Ala Ser Lys Gly Ala Gly Ala Ala Gly Ala Gly Ala Ala

325 330 335

Gly Gly Gly Pro Gly Gly Gly Gly Pro Gly Ala Gly Gly Gly Gly Gly

340 345 350

Pro Gly Ala Gly Gly Ala Gly Ser Leu Tyr Ser Asp Val Ser Thr Gly

355 360 365

Leu Thr Trp Arg Ser Gly Thr Ala Ser Ser Val Ser Tyr Pro Lys Gln

370 375 380

Met Pro Leu Ser Gln Val

385 390

<210> SEQ ID NO: 371

<211> LENGTH: 178

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 371

Lys Glu Lys Gln Gln Asn Ile Ser Pro Leu Val Arg Glu Arg Gly Pro

1 5 10 15

Gln Arg Val Ala Ala His Ile Thr Gly Thr Arg Gly Arg Ser Asn Thr

20 25 30

Leu Ser Ser Pro Asn Ser Lys Asn Glu Lys Ala Leu Gly Arg Lys Ile

35 40 45

Asn Ser Trp Glu Ser Ser Arg Ser Gly His Ser Phe Leu Ser Asn Leu

50 55 60

His Leu Arg Asn Gly Glu Leu Val Ile His Glu Lys Gly Phe Tyr Tyr

65 70 75 80

Ile Tyr Ser Gln Thr Tyr Phe Arg Phe Gln Glu Glu Ile Lys Glu Asn

85 90 95

Thr Lys Asn Asp Lys Gln Met Val Gln Tyr Ile Tyr Lys Tyr Thr Ser

100 105 110

Tyr Pro Asp Pro Ile Leu Leu Met Lys Ser Ala Arg Asn Ser Cys Trp

115 120 125

Ser Lys Asp Ala Glu Tyr Gly Leu Tyr Ser Ile Tyr Gln Gly Gly Ile

130 135 140

Phe Glu Leu Lys Glu Asn Asp Arg Ile Phe Val Ser Val Thr Asn Glu

145 150 155 160

His Leu Ile Asp Met Asp His Glu Ala Ser Phe Phe Gly Ala Phe Leu

165 170 175

Val Gly

<210> SEQ ID NO: 372

<211> LENGTH: 329

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 372

Met Leu Thr Leu Gln Thr Trp Leu Val Gln Ala Leu Phe Ile Phe Leu

1 5 10 15

Thr Thr Glu Ser Thr Gly Glu Leu Leu Asp Pro Cys Gly Tyr Ile Ser

20 25 30

Pro Glu Ser Pro Val Val Gln Leu His Ser Asn Phe Thr Ala Val Cys

35 40 45

Val Leu Lys Glu Lys Cys Met Asp Tyr Phe His Val Asn Ala Asn Tyr

50 55 60

Ile Val Trp Lys Thr Asn His Phe Thr Ile Pro Lys Glu Gln Tyr Thr

65 70 75 80

Ile Ile Asn Arg Thr Ala Ser Ser Val Thr Phe Thr Asp Ile Ala Ser

85 90 95

Leu Asn Ile Gln Leu Thr Cys Asn Ile Leu Thr Phe Gly Gln Leu Glu

100 105 110

Gln Asn Val Tyr Gly Ile Thr Ile Ile Ser Gly Leu Pro Pro Glu Lys

115 120 125

Pro Lys Asn Leu Ser Cys Ile Val Asn Glu Gly Lys Lys Met Arg Cys

130 135 140

Glu Trp Asp Gly Gly Arg Glu Thr His Leu Glu Thr Asn Phe Thr Leu

145 150 155 160

Lys Ser Glu Trp Ala Thr His Lys Phe Ala Asp Cys Lys Ala Lys Arg

165 170 175

Asp Thr Pro Thr Ser Cys Thr Val Asp Tyr Ser Thr Val Tyr Phe Val

180 185 190

Asn Ile Glu Val Trp Val Glu Ala Glu Asn Ala Leu Gly Lys Val Thr

195 200 205

Ser Asp His Ile Asn Phe Asp Pro Val Tyr Lys Val Lys Pro Asn Pro

210 215 220

Pro His Asn Leu Ser Val Ile Asn Ser Glu Glu Leu Ser Ser Ile Leu

225 230 235 240

Lys Leu Thr Trp Thr Asn Pro Ser Ile Lys Ser Val Ile Ile Leu Lys

245 250 255

Tyr Asn Ile Gln Tyr Arg Thr Lys Asp Ala Ser Thr Trp Ser Gln Ile

260 265 270

Pro Pro Glu Asp Thr Ala Ser Thr Arg Ser Ser Phe Thr Val Gln Asp

275 280 285

Leu Lys Pro Phe Thr Glu Tyr Val Phe Arg Ile Arg Cys Met Lys Glu

290 295 300

Asp Gly Lys Gly Tyr Trp Ser Asp Trp Ser Glu Glu Ala Ser Gly Ile

305 310 315 320

Thr Tyr Glu Asp Asn Ile Ala Ser Phe

325

<210> SEQ ID NO: 373

<211> LENGTH: 577

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 373

Met Leu Pro Cys Leu Val Val Leu Leu Ala Ala Leu Leu Ser Leu Arg

1 5 10 15

Leu Gly Ser Asp Ala His Gly Thr Glu Leu Pro Ser Pro Pro Ser Val

20 25 30

Trp Phe Glu Ala Glu Phe Phe His His Ile Leu His Trp Thr Pro Ile

35 40 45

Pro Asn Gln Ser Glu Ser Thr Cys Tyr Glu Val Ala Leu Leu Arg Tyr

50 55 60

Gly Ile Glu Ser Trp Asn Ser Ile Ser Asn Cys Ser Gln Thr Leu Ser

65 70 75 80

Tyr Asp Leu Thr Ala Val Thr Leu Asp Leu Tyr His Ser Asn Gly Tyr

85 90 95

Arg Ala Arg Val Arg Ala Val Asp Gly Ser Arg His Ser Asn Trp Thr

100 105 110

Val Thr Asn Thr Arg Phe Ser Val Asp Glu Val Thr Leu Thr Val Gly

115 120 125

Ser Val Asn Leu Glu Ile His Asn Gly Phe Ile Leu Gly Lys Ile Gln

130 135 140

Leu Pro Arg Pro Lys Met Ala Pro Ala Asn Asp Thr Tyr Glu Ser Ile

145 150 155 160

Phe Ser His Phe Arg Glu Tyr Glu Ile Ala Ile Arg Lys Val Pro Gly

165 170 175

Asn Phe Thr Phe Thr His Lys Lys Val Lys His Glu Asn Phe Ser Leu

180 185 190

Leu Thr Ser Gly Glu Val Gly Glu Phe Cys Val Gln Val Lys Pro Ser

195 200 205

Val Ala Ser Arg Ser Asn Lys Gly Met Trp Ser Lys Glu Glu Cys Ile

210 215 220

Ser Leu Thr Arg Gln Tyr Phe Thr Val Thr Asn Val Ile Ile Phe Phe

225 230 235 240

Ala Phe Val Leu Leu Leu Ser Gly Ala Leu Ala Tyr Cys Leu Ala Leu

245 250 255

Gln Leu Tyr Val Arg Arg Arg Lys Lys Leu Pro Ser Val Leu Leu Phe

260 265 270

Lys Lys Pro Ser Pro Phe Ile Phe Ile Ser Gln Arg Pro Ser Pro Glu

275 280 285

Thr Gln Asp Thr Ile His Pro Leu Asp Glu Glu Ala Phe Leu Lys Val

290 295 300

Ser Pro Glu Leu Lys Asn Leu Asp Leu His Gly Ser Thr Asp Ser Gly

305 310 315 320

Phe Gly Ser Thr Lys Pro Ser Leu Gln Thr Glu Glu Pro Gln Phe Leu

325 330 335

Leu Pro Asp Pro His Pro Gln Ala Asp Arg Thr Leu Gly Asn Arg Glu

340 345 350

Pro Pro Val Leu Gly Asp Ser Cys Ser Ser Gly Ser Ser Asn Ser Thr

355 360 365

Asp Ser Gly Ile Cys Leu Gln Glu Pro Ser Leu Ser Pro Ser Thr Gly

370 375 380

Pro Thr Trp Glu Gln Gln Val Gly Ser Asn Ser Arg Gly Gln Asp Asp

385 390 395 400

Ser Gly Ile Asp Leu Val Gln Asn Ser Glu Gly Arg Ala Gly Asp Thr

405 410 415

Gln Gly Gly Ser Ala Leu Gly His His Ser Pro Pro Glu Pro Glu Val

420 425 430

Pro Gly Glu Glu Asp Pro Ala Ala Val Ala Phe Gln Gly Tyr Leu Arg

435 440 445

Gln Thr Arg Cys Ala Glu Glu Lys Ala Thr Lys Thr Gly Cys Leu Glu

450 455 460

Glu Glu Ser Pro Leu Thr Asp Gly Leu Gly Pro Lys Phe Gly Arg Cys

465 470 475 480

Leu Val Asp Glu Ala Gly Leu His Pro Pro Ala Leu Ala Lys Gly Tyr

485 490 495

Leu Lys Gln Asp Pro Leu Glu Met Thr Leu Ala Ser Ser Gly Ala Pro

500 505 510

Thr Gly Gln Trp Asn Gln Pro Thr Glu Glu Trp Ser Leu Leu Ala Leu

515 520 525

Ser Ser Cys Ser Asp Leu Gly Ile Ser Asp Trp Ser Phe Ala His Asp

530 535 540

Leu Ala Pro Leu Gly Cys Val Ala Ala Pro Gly Gly Leu Leu Gly Ser

545 550 555 560

Phe Asn Ser Asp Leu Val Thr Leu Pro Leu Ile Ser Ser Leu Gln Ser

565 570 575

Ser

<210> SEQ ID NO: 374

<211> LENGTH: 656

<212> TYPE: PRT

<213> ORGANISM: Drosophila melanogaster

<400> SEQENCE: 374

Lys Ile Cys Ile Gly Thr Lys Ser Arg Leu Ser Val Pro Ser Asn Lys

1 5 10 15

Glu His His Tyr Arg Asn Leu Arg Asp Arg Tyr Thr Asn Cys Thr Tyr

20 25 30

Val Asp Gly Asn Leu Glu Leu Thr Trp Leu Pro Asn Glu Asn Leu Asp

35 40 45

Leu Ser Phe Leu Asp Asn Ile Arg Glu Val Thr Gly Tyr Ile Leu Ile

50 55 60

Ser His Val Asp Val Lys Lys Val Val Phe Pro Lys Leu Gln Ile Ile

65 70 75 80

Arg Gly Arg Thr Leu Phe Ser Leu Ser Val Glu Glu Glu Lys Tyr Ala

85 90 95

Leu Phe Val Thr Tyr Ser Lys Met Tyr Thr Leu Glu Ile Pro Asp Leu

100 105 110

Arg Asp Val Leu Asn Gly Gln Val Gly Phe His Asn Asn Tyr Asn Leu

115 120 125

Cys His Met Arg Thr Ile Gln Trp Ser Glu Ile Val Ser Asn Gly Thr

130 135 140

Asp Ala Tyr Tyr Asn Tyr Asp Phe Thr Ala Pro Glu Arg Glu Cys Pro

145 150 155 160

Lys Cys His Glu Ser Cys Thr His Gly Cys Trp Gly Glu Gly Pro Lys

165 170 175

Asn Cys Gln Lys Phe Ser Lys Leu Thr Cys Ser Pro Gln Cys Ala Gly

180 185 190

Gly Arg Cys Tyr Gly Pro Lys Pro Arg Glu Cys Cys His Leu Phe Cys

195 200 205

Ala Gly Gly Cys Thr Gly Pro Thr Gln Lys Asp Cys Ile Ala Cys Lys

210 215 220

Asn Phe Phe Asp Glu Gly Val Cys Lys Glu Glu Cys Pro Pro Met Arg

225 230 235 240

Lys Tyr Asn Pro Thr Thr Tyr Val Leu Glu Thr Asn Pro Glu Gly Lys

245 250 255

Tyr Ala Tyr Gly Ala Thr Cys Val Lys Glu Cys Pro Gly His Leu Leu

260 265 270

Arg Asp Asn Gly Ala Cys Val Arg Ser Cys Pro Gln Asp Lys Met Asp

275 280 285

Lys Gly Gly Glu Cys Val Pro Cys Asn Gly Pro Cys Pro Lys Thr Cys

290 295 300

Pro Gly Val Thr Val Leu His Ala Gly Asn Ile Asp Ser Phe Arg Asn

305 310 315 320

Cys Thr Val Ile Asp Gly Asn Ile Arg Ile Leu Asp Gln Thr Phe Ser

325 330 335

Gly Phe Gln Asp Val Tyr Ala Asn Tyr Thr Met Gly Pro Arg Tyr Ile

340 345 350

Pro Leu Asp Pro Glu Arg Leu Glu Val Phe Ser Thr Val Lys Glu Ile

355 360 365

Thr Gly Tyr Leu Asn Ile Glu Gly Thr His Pro Gln Phe Arg Asn Leu

370 375 380

Ser Tyr Phe Arg Asn Leu Glu Thr Ile His Gly Arg Gln Leu Met Glu

385 390 395 400

Ser Met Phe Ala Ala Leu Ala Ile Val Lys Ser Ser Leu Tyr Ser Leu

405 410 415

Glu Met Arg Asn Leu Lys Gln Ile Ser Ser Gly Ser Val Val Ile Gln

420 425 430

His Asn Arg Asp Leu Cys Tyr Val Ser Asn Ile Arg Trp Pro Ala Ile

435 440 445

Gln Lys Glu Pro Glu Gln Lys Val Trp Val Asn Glu Asn Leu Arg Ala

450 455 460

Asp Leu Cys Glu Lys Asn Gly Thr Ile Cys Ser Asp Gln Cys Asn Glu

465 470 475 480

Asp Gly Cys Trp Gly Ala Gly Thr Asp Gln Cys Leu Asn Cys Lys Asn

485 490 495

Phe Asn Phe Asn Gly Thr Cys Ile Ala Asp Cys Gly Tyr Ile Ser Asn

500 505 510

Ala Tyr Lys Phe Asp Asn Arg Thr Cys Lys Ile Cys His Pro Glu Cys

515 520 525

Arg Thr Cys Asn Gly Ala Gly Ala Asp His Cys Gln Glu Cys Val His

530 535 540

Val Arg Asp Gly Gln His Cys Val Ser Glu Cys Pro Lys Asn Lys Tyr

545 550 555 560

Asn Asp Arg Gly Val Cys Arg Glu Cys His Ala Thr Cys Asp Gly Cys

565 570 575

Thr Gly Pro Lys Asp Thr Ile Gly Ile Gly Ala Cys Thr Thr Cys Asn

580 585 590

Leu Ala Ile Ile Asn Asn Asp Ala Thr Val Lys Arg Cys Leu Leu Lys

595 600 605

Asp Asp Lys Cys Pro Asp Gly Tyr Phe Trp Glu Tyr Val His Pro Gln

610 615 620

Glu Gln Gly Ser Leu Lys Pro Leu Ala Gly Arg Ala Val Cys Arg Lys

625 630 635 640

Cys His Pro Leu Cys Glu Leu Cys Thr Asn Tyr Gly Tyr His Glu Gln

645 650 655

<210> SEQ ID NO: 375

<211> LENGTH: 326

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 375

Met Glu Lys Asp Gly Leu Cys Arg Ala Asp Gln Gln Tyr Glu Cys Val

1 5 10 15

Ala Glu Ile Gly Glu Gly Ala Tyr Gly Lys Val Phe Lys Ala Arg Asp

20 25 30

Leu Lys Asn Gly Gly Arg Phe Val Ala Leu Lys Arg Val Arg Val Gln

35 40 45

Thr Gly Glu Glu Gly Met Pro Leu Ser Thr Ile Arg Glu Val Ala Val

50 55 60

Leu Arg His Leu Glu Thr Phe Glu His Pro Asn Val Val Arg Leu Phe

65 70 75 80

Asp Val Cys Thr Val Ser Arg Thr Asp Arg Glu Thr Lys Leu Thr Leu

85 90 95

Val Phe Glu His Val Asp Gln Asp Leu Thr Thr Tyr Leu Asp Lys Val

100 105 110

Pro Glu Pro Gly Val Pro Thr Glu Thr Ile Lys Asp Met Met Phe Gln

115 120 125

Leu Leu Arg Gly Leu Asp Phe Leu His Ser His Arg Val Val His Arg

130 135 140

Asp Leu Lys Pro Gln Asn Ile Leu Val Thr Ser Ser Gly Gln Ile Lys

145 150 155 160

Leu Ala Asp Phe Gly Leu Ala Arg Ile Tyr Ser Phe Gln Met Ala Leu

165 170 175

Thr Ser Val Val Val Thr Leu Trp Tyr Arg Ala Pro Glu Val Leu Leu

180 185 190

Gln Ser Ser Tyr Ala Thr Pro Val Asp Leu Trp Ser Val Gly Cys Ile

195 200 205

Phe Ala Glu Met Phe Arg Arg Lys Pro Leu Phe Arg Gly Ser Ser Asp

210 215 220

Val Asp Gln Leu Gly Lys Ile Leu Asp Val Ile Gly Leu Pro Gly Glu

225 230 235 240

Glu Asp Trp Pro Arg Asp Val Ala Leu Pro Arg Gln Ala Phe His Ser

245 250 255

Lys Ser Ala Gln Pro Ile Glu Lys Phe Val Thr Asp Ile Asp Glu Leu

260 265 270

Gly Lys Asp Leu Leu Leu Lys Cys Leu Thr Phe Asn Pro Ala Lys Arg

275 280 285

Ile Ser Ala Tyr Ser Ala Leu Ser His Pro Tyr Phe Gln Asp Leu Glu

290 295 300

Arg Cys Lys Glu Asn Leu Asp Ser His Leu Pro Pro Ser Gln Asn Thr

305 310 315 320

Ser Glu Leu Asn Thr Ala

325

<210> SEQ ID NO: 376

<211> LENGTH: 119

<212> TYPE: PRT

<213> ORGANISM: Paramecium bursaria Chlorella virus 1

<400> SEQENCE: 376

Met Phe Asn Asp Arg Val Ile Val Lys Lys Ser Pro Leu Gly Gly Tyr

1 5 10 15

Gly Val Phe Ala Arg Lys Ser Phe Glu Lys Gly Glu Leu Val Glu Glu

20 25 30

Cys Leu Cys Ile Val Arg His Asn Asp Asp Trp Gly Thr Ala Leu Glu

35 40 45

Asp Tyr Leu Phe Ser Arg Lys Asn Met Ser Ala Met Ala Leu Gly Phe

50 55 60

Gly Ala Ile Phe Asn His Ser Lys Asp Pro Asn Ala Arg His Glu Leu

65 70 75 80

Thr Ala Gly Leu Lys Arg Met Arg Ile Phe Thr Ile Lys Pro Ile Ala

85 90 95

Ile Gly Glu Glu Ile Thr Ile Ser Tyr Gly Asp Asp Tyr Trp Leu Ser

100 105 110

Arg Pro Arg Leu Thr Gln Asn

115

<210> SEQ ID NO: 377

<211> LENGTH: 293

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 377

Met Trp Pro Leu Val Ala Ala Leu Leu Leu Gly Ser Ala Cys Cys Gly

1 5 10 15

Ser Ala Gln Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe

20 25 30

Cys Asn Asp Thr Val Val Ile Pro Cys Phe Val Thr Asn Met Glu Ala

35 40 45

Gln Asn Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp

50 55 60

Ile Tyr Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp

65 70 75 80

Phe Ser Ser Ala Lys Ile Glu Val Ser Gln Leu Leu Lys Gly Asp Ala

85 90 95

Ser Leu Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr

100 105 110

Thr Cys Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr Ile Ile Glu

115 120 125

Leu Lys Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn Ile Leu

130 135 140

Ile Val Ile Phe Pro Ile Phe Ala Ile Leu Leu Phe Trp Gly Gln Phe

145 150 155 160

Gly Ile Lys Thr Leu Lys Tyr Arg Ser Gly Gly Met Asp Glu Lys Thr

165 170 175

Ile Ala Leu Leu Val Ala Gly Leu Val Ile Thr Val Ile Val Ile Val

180 185 190

Gly Ala Ile Leu Phe Val Pro Gly Glu Tyr Ser Leu Lys Asn Ala Thr

195 200 205

Gly Leu Gly Leu Ile Val Thr Ser Thr Gly Ile Leu Ile Leu Leu His

210 215 220

Tyr Tyr Val Phe Ser Thr Ala Ile Gly Leu Thr Ser Phe Val Ile Ala

225 230 235 240

Ile Leu Val Ile Gln Val Ile Ala Tyr Ile Leu Ala Val Val Gly Leu

245 250 255

Ser Leu Cys Ile Ala Ala Cys Ile Pro Met His Gly Pro Leu Leu Ile

260 265 270

Ser Gly Leu Ser Ile Leu Ala Leu Ala Gln Leu Leu Gly Leu Val Tyr

275 280 285

Met Lys Phe Val Glu

290

<210> SEQ ID NO: 378

<211> LENGTH: 507

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 378

Met Glu Pro Ala Gly Pro Ala Pro Gly Arg Leu Gly Pro Leu Leu Cys

1 5 10 15

Leu Leu Leu Ala Ala Ser Cys Ala Trp Ser Gly Val Ala Gly Glu Glu

20 25 30

Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Val Ser Val Ala Ala Gly

35 40 45

Glu Ser Ala Ile Leu His Cys Thr Val Thr Ser Leu Ile Pro Val Gly

50 55 60

Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Ala Arg Glu Leu Ile Tyr

65 70 75 80

Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser Glu Ser

85 90 95

Thr Lys Arg Glu Asn Met Asp Phe Ser Ile Ser Ile Ser Asn Ile Thr

100 105 110

Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser

115 120 125

Pro Asp Thr Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu Ser Val Arg

130 135 140

Ala Lys Pro Ser Ala Pro Val Val Ser Gly Pro Ala Ala Arg Ala Thr

145 150 155 160

Pro Gln His Thr Val Ser Phe Thr Cys Glu Ser His Gly Phe Ser Pro

165 170 175

Arg Asp Ile Thr Leu Lys Trp Phe Lys Asn Gly Asn Glu Leu Ser Asp

180 185 190

Phe Gln Thr Asn Val Asp Pro Val Gly Glu Ser Val Ser Tyr Ser Ile

195 200 205

His Ser Thr Ala Lys Val Val Leu Thr Arg Glu Asp Val His Ser Gln

210 215 220

Val Ile Cys Glu Val Ala His Val Thr Leu Gln Gly Asp Pro Leu Arg

225 230 235 240

Gly Thr Ala Asn Leu Ser Glu Thr Ile Arg Val Pro Pro Thr Leu Glu

245 250 255

Val Thr Gln Gln Pro Val Arg Ala Glu Asn Gln Val Asn Val Thr Cys

260 265 270

Gln Val Arg Lys Phe Tyr Pro Gln Arg Leu Gln Leu Thr Trp Leu Glu

275 280 285

Asn Gly Asn Val Ser Arg Thr Glu Thr Ala Ser Thr Val Thr Glu Asn

290 295 300

Lys Asp Gly Thr Tyr Asn Trp Met Ser Trp Leu Leu Val Asn Val Ser

305 310 315 320

Ala His Arg Asp Asp Val Lys Leu Thr Cys Gln Val Glu His Asp Gly

325 330 335

Gln Pro Ala Val Ser Lys Ser His Asp Leu Lys Val Ser Ala His Pro

340 345 350

Lys Glu Gln Gly Ser Asn Thr Ala Ala Glu Asn Thr Gly Ser Asn Glu

355 360 365

Arg Asn Ile Tyr Ile Val Val Gly Val Val Cys Thr Leu Leu Val Ala

370 375 380

Leu Leu Met Ala Ala Leu Tyr Leu Val Arg Ile Arg Gln Lys Lys Ala

385 390 395 400

Gln Gly Ser Thr Ser Ser Thr Arg Leu His Glu Pro Glu Lys Asn Ala

405 410 415

Arg Glu Ile Thr Gln Val Gln Ser Leu Asp Thr Asn Asp Ile Thr Tyr

420 425 430

Ala Asp Leu Asn Leu Pro Lys Gly Lys Lys Pro Ala Pro Gln Ala Ala

435 440 445

Glu Pro Asn Asn His Thr Glu Tyr Ala Ser Ile Gln Thr Ser Pro Gln

450 455 460

Pro Ala Ser Glu Asp Thr Leu Thr Tyr Ala Asp Leu Asp Met Val His

465 470 475 480

Leu Asn Arg Thr Pro Lys Gln Pro Ala Pro Lys Pro Glu Pro Ser Phe

485 490 495

Ser Glu Tyr Ala Ser Val Gln Val Pro Arg Lys

500 505

<210> SEQ ID NO: 379

<211> LENGTH: 1456

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 379

Met Arg Leu Pro Leu Leu Leu Val Phe Ala Ser Val Ile Pro Gly Ala

1 5 10 15

Val Leu Leu Leu Asp Thr Arg Gln Phe Leu Ile Tyr Asn Glu Asp His

20 25 30

Lys Arg Cys Val Asp Ala Val Ser Pro Ser Ala Val Gln Thr Ala Ala

35 40 45

Cys Asn Gln Asp Ala Glu Ser Gln Lys Phe Arg Trp Val Ser Glu Ser

50 55 60

Gln Ile Met Ser Val Ala Phe Lys Leu Cys Leu Gly Val Pro Ser Lys

65 70 75 80

Thr Asp Trp Val Ala Ile Thr Leu Tyr Ala Cys Asp Ser Lys Ser Glu

85 90 95

Phe Gln Lys Trp Glu Cys Lys Asn Asp Thr Leu Leu Gly Ile Lys Gly

100 105 110

Glu Asp Leu Phe Phe Asn Tyr Gly Asn Arg Gln Glu Lys Asn Ile Met

115 120 125

Leu Tyr Lys Gly Ser Gly Leu Trp Ser Arg Trp Lys Ile Tyr Gly Thr

130 135 140

Thr Asp Asn Leu Cys Ser Arg Gly Tyr Glu Ala Met Tyr Thr Leu Leu

145 150 155 160

Gly Asn Ala Asn Gly Ala Thr Cys Ala Phe Pro Phe Lys Phe Glu Asn

165 170 175

Lys Trp Tyr Ala Asp Cys Thr Ser Ala Gly Arg Ser Asp Gly Trp Leu

180 185 190

Trp Cys Gly Thr Thr Thr Asp Tyr Asp Thr Asp Lys Leu Phe Gly Tyr

195 200 205

Cys Pro Leu Lys Phe Glu Gly Ser Glu Ser Leu Trp Asn Lys Asp Pro

210 215 220

Leu Thr Ser Val Ser Tyr Gln Ile Asn Ser Lys Ser Ala Leu Thr Trp

225 230 235 240

His Gln Ala Arg Lys Ser Cys Gln Gln Gln Asn Ala Glu Leu Leu Ser

245 250 255

Ile Thr Glu Ile His Glu Gln Thr Tyr Leu Thr Gly Leu Thr Ser Ser

260 265 270

Leu Thr Ser Gly Leu Trp Ile Gly Leu Asn Ser Leu Ser Phe Asn Ser

275 280 285

Gly Trp Gln Trp Ser Asp Arg Ser Pro Phe Arg Tyr Leu Asn Trp Leu

290 295 300

Pro Gly Ser Pro Ser Ala Glu Pro Gly Lys Ser Cys Val Ser Leu Asn

305 310 315 320

Pro Gly Lys Asn Ala Lys Trp Glu Asn Leu Glu Cys Val Gln Lys Leu

325 330 335

Gly Tyr Ile Cys Lys Lys Gly Asn Thr Thr Leu Asn Ser Phe Val Ile

340 345 350

Pro Ser Glu Ser Asp Val Pro Thr His Cys Pro Ser Gln Trp Trp Pro

355 360 365

Tyr Ala Gly His Cys Tyr Lys Ile His Arg Asp Glu Lys Lys Ile Gln

370 375 380

Arg Asp Ala Leu Thr Thr Cys Arg Lys Glu Gly Gly Asp Leu Thr Ser

385 390 395 400

Ile His Thr Ile Glu Glu Leu Asp Phe Ile Ile Ser Gln Leu Gly Tyr

405 410 415

Glu Pro Asn Asp Glu Leu Trp Ile Gly Leu Asn Asp Ile Lys Ile Gln

420 425 430

Met Tyr Phe Glu Trp Ser Asp Gly Thr Pro Val Thr Phe Thr Lys Trp

435 440 445

Leu Arg Gly Glu Pro Ser His Glu Asn Asn Arg Gln Glu Asp Cys Val

450 455 460

Val Met Lys Gly Lys Asp Gly Tyr Trp Ala Asp Arg Gly Cys Glu Trp

465 470 475 480

Pro Leu Gly Tyr Ile Cys Lys Met Lys Ser Arg Ser Gln Gly Pro Glu

485 490 495

Ile Val Glu Val Glu Lys Gly Cys Arg Lys Gly Trp Lys Lys His His

500 505 510

Phe Tyr Cys Tyr Met Ile Gly His Thr Leu Ser Thr Phe Ala Glu Ala

515 520 525

Asn Gln Thr Cys Asn Asn Glu Asn Ala Tyr Leu Thr Thr Ile Glu Asp

530 535 540

Arg Tyr Glu Gln Ala Phe Leu Thr Ser Phe Val Gly Leu Arg Pro Glu

545 550 555 560

Lys Tyr Phe Trp Thr Gly Leu Ser Asp Ile Gln Thr Lys Gly Thr Phe

565 570 575

Gln Trp Thr Ile Glu Glu Glu Val Arg Phe Thr His Trp Asn Ser Asp

580 585 590

Met Pro Gly Arg Lys Pro Gly Cys Val Ala Met Arg Thr Gly Ile Ala

595 600 605

Gly Gly Leu Trp Asp Val Leu Lys Cys Asp Glu Lys Ala Lys Phe Val

610 615 620

Cys Lys His Trp Ala Glu Gly Val Thr His Pro Pro Lys Pro Thr Thr

625 630 635 640

Thr Pro Glu Pro Lys Cys Pro Glu Asp Trp Gly Ala Ser Ser Arg Thr

645 650 655

Ser Leu Cys Phe Lys Leu Tyr Ala Lys Gly Lys His Glu Lys Lys Thr

660 665 670

Trp Phe Glu Ser Arg Asp Phe Cys Arg Ala Leu Gly Gly Asp Leu Ala

675 680 685

Ser Ile Asn Asn Lys Glu Glu Gln Gln Thr Ile Trp Arg Leu Ile Thr

690 695 700

Ala Ser Gly Ser Tyr His Lys Leu Phe Trp Leu Gly Leu Thr Tyr Gly

705 710 715 720

Ser Pro Ser Glu Gly Phe Thr Trp Ser Asp Gly Ser Pro Val Ser Tyr

725 730 735

Glu Asn Trp Ala Tyr Gly Glu Pro Asn Asn Tyr Gln Asn Val Glu Tyr

740 745 750

Cys Gly Glu Leu Lys Gly Asp Pro Thr Met Ser Trp Asn Asp Ile Asn

755 760 765

Cys Glu His Leu Asn Asn Trp Ile Cys Gln Ile Gln Lys Gly Gln Thr

770 775 780

Pro Lys Pro Glu Pro Thr Pro Ala Pro Gln Asp Asn Pro Pro Val Thr

785 790 795 800

Glu Asp Gly Trp Val Ile Tyr Lys Asp Tyr Gln Tyr Tyr Phe Ser Lys

805 810 815

Glu Lys Glu Thr Met Asp Asn Ala Arg Ala Phe Cys Lys Arg Asn Phe

820 825 830

Gly Asp Leu Val Ser Ile Gln Ser Glu Ser Glu Lys Lys Phe Leu Trp

835 840 845

Lys Tyr Val Asn Arg Asn Asp Ala Gln Ser Ala Tyr Phe Ile Gly Leu

850 855 860

Leu Ile Ser Leu Asp Lys Lys Phe Ala Trp Met Asp Gly Ser Lys Val

865 870 875 880

Asp Tyr Val Ser Trp Ala Thr Gly Glu Pro Asn Phe Ala Asn Glu Asp

885 890 895

Glu Asn Cys Val Thr Met Tyr Ser Asn Ser Gly Phe Trp Asn Asp Ile

900 905 910

Asn Cys Gly Tyr Pro Asn Ala Phe Ile Cys Gln Arg His Asn Ser Ser

915 920 925

Ile Asn Ala Thr Thr Val Met Pro Thr Met Pro Ser Val Pro Ser Gly

930 935 940

Cys Lys Glu Gly Trp Asn Phe Tyr Ser Asn Lys Cys Phe Lys Ile Phe

945 950 955 960

Gly Phe Met Glu Glu Glu Arg Lys Asn Trp Gln Glu Ala Arg Lys Ala

965 970 975

Cys Ile Gly Phe Gly Gly Asn Leu Val Ser Ile Gln Asn Glu Lys Glu

980 985 990

Gln Ala Phe Leu Thr Tyr His Met Lys Asp Ser Thr Phe Ser Ala Trp

995 1000 1005

Thr Gly Leu Asn Asp Val Asn Ser Glu His Thr Phe Leu Trp Thr

1010 1015 1020

Asp Gly Arg Gly Val His Tyr Thr Asn Trp Gly Lys Gly Tyr Pro

1025 1030 1035

Gly Gly Arg Arg Ser Ser Leu Ser Tyr Glu Asp Ala Asp Cys Val

1040 1045 1050

Val Ile Ile Gly Gly Ala Ser Asn Glu Ala Gly Lys Trp Met Asp

1055 1060 1065

Asp Thr Cys Asp Ser Lys Arg Gly Tyr Ile Cys Gln Thr Arg Ser

1070 1075 1080

Asp Pro Ser Leu Thr Asn Pro Pro Ala Thr Ile Gln Thr Asp Gly

1085 1090 1095

Phe Val Lys Tyr Gly Lys Ser Ser Tyr Ser Leu Met Arg Gln Lys

1100 1105 1110

Phe Gln Trp His Glu Ala Glu Thr Tyr Cys Lys Leu His Asn Ser

1115 1120 1125

Leu Ile Ala Ser Ile Leu Asp Pro Tyr Ser Asn Ala Phe Ala Trp

1130 1135 1140

Leu Gln Met Glu Thr Ser Asn Glu Arg Val Trp Ile Ala Leu Asn

1145 1150 1155

Ser Asn Leu Thr Asp Asn Gln Tyr Thr Trp Thr Asp Lys Trp Arg

1160 1165 1170

Val Arg Tyr Thr Asn Trp Ala Ala Asp Glu Pro Lys Leu Lys Ser

1175 1180 1185

Ala Cys Val Tyr Leu Asp Leu Asp Gly Tyr Trp Lys Thr Ala His

1190 1195 1200

Cys Asn Glu Ser Phe Tyr Phe Leu Cys Lys Arg Ser Asp Glu Ile

1205 1210 1215

Pro Ala Thr Glu Pro Pro Gln Leu Pro Gly Arg Cys Pro Glu Ser

1220 1225 1230

Asp His Thr Ala Trp Ile Pro Phe His Gly His Cys Tyr Tyr Ile

1235 1240 1245

Glu Ser Ser Tyr Thr Arg Asn Trp Gly Gln Ala Ser Leu Glu Cys

1250 1255 1260

Leu Arg Met Gly Ser Ser Leu Val Ser Ile Glu Ser Ala Ala Glu

1265 1270 1275

Ser Ser Phe Leu Ser Tyr Arg Val Glu Pro Leu Lys Ser Lys Thr

1280 1285 1290

Asn Phe Trp Ile Gly Leu Phe Arg Asn Val Glu Gly Thr Trp Leu

1295 1300 1305

Trp Ile Asn Asn Ser Pro Val Ser Phe Val Asn Trp Asn Thr Gly

1310 1315 1320

Asp Pro Ser Gly Glu Arg Asn Asp Cys Val Ala Leu His Ala Ser

1325 1330 1335

Ser Gly Phe Trp Ser Asn Ile His Cys Ser Ser Tyr Lys Gly Tyr

1340 1345 1350

Ile Cys Lys Arg Pro Lys Ile Ile Asp Ala Lys Pro Thr His Glu

1355 1360 1365

Leu Leu Thr Thr Lys Ala Asp Thr Arg Lys Met Asp Pro Ser Lys

1370 1375 1380

Pro Ser Ser Asn Val Ala Gly Val Val Ile Ile Val Ile Leu Leu

1385 1390 1395

Ile Leu Thr Gly Ala Gly Leu Ala Ala Tyr Phe Phe Tyr Lys Lys

1400 1405 1410

Arg Arg Val His Leu Pro Gln Glu Gly Ala Phe Glu Asn Thr Leu

1415 1420 1425

Tyr Phe Asn Ser Gln Ser Ser Pro Gly Thr Ser Asp Met Lys Asp

1430 1435 1440

Leu Val Gly Asn Ile Glu Gln Asn Glu His Ser Val Ile

1445 1450 1455

<210> SEQ ID NO: 380

<211> LENGTH: 684

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 380

Met Met Asp Ala Ser Lys Glu Leu Gln Val Leu His Ile Asp Phe Leu

1 5 10 15

Asn Gln Asp Asn Ala Val Ser His His Thr Trp Glu Phe Gln Thr Ser

20 25 30

Ser Pro Val Phe Arg Arg Gly Gln Val Phe His Leu Arg Leu Val Leu

35 40 45

Asn Gln Pro Leu Gln Ser Tyr His Gln Leu Lys Leu Glu Phe Ser Thr

50 55 60

Gly Pro Asn Pro Ser Ile Ala Lys His Thr Leu Val Val Leu Asp Pro

65 70 75 80

Arg Thr Pro Ser Asp His Tyr Asn Trp Gln Ala Thr Leu Gln Asn Glu

85 90 95

Ser Gly Lys Glu Val Thr Val Ala Val Thr Ser Ser Pro Asn Ala Ile

100 105 110

Leu Gly Lys Tyr Gln Leu Asn Val Lys Thr Gly Asn His Ile Leu Lys

115 120 125

Ser Glu Glu Asn Ile Leu Tyr Leu Leu Phe Asn Pro Trp Cys Lys Glu

130 135 140

Asp Met Val Phe Met Pro Asp Glu Asp Glu Arg Lys Glu Tyr Ile Leu

145 150 155 160

Asn Asp Thr Gly Cys His Tyr Val Gly Ala Ala Arg Ser Ile Lys Cys

165 170 175

Lys Pro Trp Asn Phe Gly Gln Phe Glu Lys Asn Val Leu Asp Cys Cys

180 185 190

Ile Ser Leu Leu Thr Glu Ser Ser Leu Lys Pro Thr Asp Arg Arg Asp

195 200 205

Pro Val Leu Val Cys Arg Ala Met Cys Ala Met Met Ser Phe Glu Lys

210 215 220

Gly Gln Gly Val Leu Ile Gly Asn Trp Thr Gly Asp Tyr Glu Gly Gly

225 230 235 240

Thr Ala Pro Tyr Lys Trp Thr Gly Ser Ala Pro Ile Leu Gln Gln Tyr

245 250 255

Tyr Asn Thr Lys Gln Ala Val Cys Phe Gly Gln Cys Trp Val Phe Ala

260 265 270

Gly Ile Leu Thr Thr Val Leu Arg Ala Leu Gly Ile Pro Ala Arg Ser

275 280 285

Val Thr Gly Phe Asp Ser Ala His Asp Thr Glu Arg Asn Leu Thr Val

290 295 300

Asp Thr Tyr Val Asn Glu Asn Gly Glu Lys Ile Thr Ser Met Thr His

305 310 315 320

Asp Ser Val Trp Asn Phe His Val Trp Thr Asp Ala Trp Met Lys Arg

325 330 335

Pro Asp Leu Pro Lys Gly Tyr Asp Gly Trp Gln Ala Val Asp Ala Thr

340 345 350

Pro Gln Glu Arg Ser Gln Gly Val Phe Cys Cys Gly Pro Ser Pro Leu

355 360 365

Thr Ala Ile Arg Lys Gly Asp Ile Phe Ile Val Tyr Asp Thr Arg Phe

370 375 380

Val Phe Ser Glu Val Asn Gly Asp Arg Leu Ile Trp Leu Val Lys Met

385 390 395 400

Val Asn Gly Gln Glu Glu Leu His Val Ile Ser Met Glu Thr Thr Ser

405 410 415

Ile Gly Lys Asn Ile Ser Thr Lys Ala Val Gly Gln Asp Arg Arg Arg

420 425 430

Asp Ile Thr Tyr Glu Tyr Lys Tyr Pro Glu Gly Ser Ser Glu Glu Arg

435 440 445

Gln Val Met Asp His Ala Phe Leu Leu Leu Ser Ser Glu Arg Glu His

450 455 460

Arg Arg Pro Val Lys Glu Asn Phe Leu His Met Ser Val Gln Ser Asp

465 470 475 480

Asp Val Leu Leu Gly Asn Ser Val Asn Phe Thr Val Ile Leu Lys Arg

485 490 495

Lys Thr Ala Ala Leu Gln Asn Val Asn Ile Leu Gly Ser Phe Glu Leu

500 505 510

Gln Leu Tyr Thr Gly Lys Lys Met Ala Lys Leu Cys Asp Leu Asn Lys

515 520 525

Thr Ser Gln Ile Gln Gly Gln Val Ser Glu Val Thr Leu Thr Leu Asp

530 535 540

Ser Lys Thr Tyr Ile Asn Ser Leu Ala Ile Leu Asp Asp Glu Pro Val

545 550 555 560

Ile Arg Gly Phe Ile Ile Ala Glu Ile Val Glu Ser Lys Glu Ile Met

565 570 575

Ala Ser Glu Val Phe Thr Ser Phe Gln Tyr Pro Glu Phe Ser Ile Glu

580 585 590

Leu Pro Asn Thr Gly Arg Ile Gly Gln Leu Leu Val Cys Asn Cys Ile

595 600 605

Phe Lys Asn Thr Leu Ala Ile Pro Leu Thr Asp Val Lys Phe Ser Leu

610 615 620

Glu Ser Leu Gly Ile Ser Ser Leu Gln Thr Ser Asp His Gly Thr Val

625 630 635 640

Gln Pro Gly Glu Thr Ile Gln Ser Gln Ile Lys Cys Thr Pro Ile Lys

645 650 655

Thr Gly Pro Lys Lys Phe Ile Val Lys Leu Ser Ser Lys Gln Val Lys

660 665 670

Glu Ile Asn Ala Gln Lys Ile Val Leu Ile Thr Lys

675 680

<210> SEQ ID NO: 381

<211> LENGTH: 585

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 381

Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu

1 5 10 15

Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln

20 25 30

Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu

35 40 45

Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys

50 55 60

Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu

65 70 75 80

Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro

85 90 95

Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu

100 105 110

Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His

115 120 125

Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg

130 135 140

Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg

145 150 155 160

Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala

165 170 175

Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser

180 185 190

Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu

195 200 205

Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro

210 215 220

Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys

225 230 235 240

Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp

245 250 255

Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser

260 265 270

Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His

275 280 285

Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser

290 295 300

Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala

305 310 315 320

Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg

325 330 335

Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr

340 345 350

Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu

355 360 365

Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro

370 375 380

Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu

385 390 395 400

Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro

405 410 415

Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys

420 425 430

Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys

435 440 445

Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His

450 455 460

Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser

465 470 475 480

Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr

485 490 495

Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp

500 505 510

Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala

515 520 525

Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu

530 535 540

Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys

545 550 555 560

Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val

565 570 575

Ala Ala Ser Gln Ala Ala Leu Gly Leu

580 585

<210> SEQ ID NO: 382

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 382

Ile Glu Ser Lys Arg Arg Lys Lys Lys Pro

1 5 10

<210> SEQ ID NO: 383

<211> LENGTH: 10

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 383

Ala Pro Gly Pro Gly Asp Gly Gly Thr Ala

1 5 10

<210> SEQ ID NO: 384

<211> LENGTH: 11

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 384

Phe Ala Lys Lys Phe Ala Lys Lys Phe Lys Cys

1 5 10

<210> SEQ ID NO: 385

<211> LENGTH: 11

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 385

Lys Phe Arg Lys Ala Phe Lys Arg Phe Phe Cys

1 5 10

<210> SEQ ID NO: 386

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 386

Lys Phe Phe Lys

1

<210> SEQ ID NO: 387

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 387

Lys Trp Trp Lys

1

<210> SEQ ID NO: 388

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 388

Lys Tyr Tyr Lys

1

<210> SEQ ID NO: 389

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 389

Lys Phe Trp Lys

1

<210> SEQ ID NO: 390

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 390

Lys Trp Phe Lys

1

<210> SEQ ID NO: 391

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 391

Lys Phe Tyr Lys

1

<210> SEQ ID NO: 392

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 392

Lys Tyr Phe Lys

1

<210> SEQ ID NO: 393

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 393

Lys Trp Tyr Lys

1

<210> SEQ ID NO: 394

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 394

Lys Tyr Trp Lys

1

<210> SEQ ID NO: 395

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 395

Arg Phe Phe Arg

1

<210> SEQ ID NO: 396

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 396

Arg Trp Trp Arg

1

<210> SEQ ID NO: 397

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 397

Arg Tyr Tyr Arg

1

<210> SEQ ID NO: 398

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 398

Arg Phe Trp Arg

1

<210> SEQ ID NO: 399

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 399

Arg Trp Phe Arg

1

<210> SEQ ID NO: 400

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 400

Arg Phe Tyr Arg

1

<210> SEQ ID NO: 401

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 401

Arg Tyr Phe Arg

1

<210> SEQ ID NO: 402

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 402

Arg Trp Tyr Arg

1

<210> SEQ ID NO: 403

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 403

Arg Tyr Trp Arg

1

<210> SEQ ID NO: 404

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 404

His Phe Phe His

1

<210> SEQ ID NO: 405

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 405

His Trp Trp His

1

<210> SEQ ID NO: 406

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 406

His Tyr Tyr His

1

<210> SEQ ID NO: 407

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 407

His Phe Trp His

1

<210> SEQ ID NO: 408

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 408

His Trp Phe His

1

<210> SEQ ID NO: 409

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 409

His Phe Tyr His

1

<210> SEQ ID NO: 410

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 410

His Tyr Phe His

1

<210> SEQ ID NO: 411

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 411

His Trp Tyr His

1

<210> SEQ ID NO: 412

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 412

Gly Gly Gly Arg

1

<210> SEQ ID NO: 413

<211> LENGTH: 4

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Synthetic peptide

<400> SEQENCE: 413

Gly Pro Gly Arg

1

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Citation

Patents Cited in This Cited by
Title Current Assignee Application Date Publication Date
Ubiquitin-lytic peptide fusion gene constructs, protein products deriving therefrom, and methods of making and using same DEMEGEN, INC. 21 July 1995 21 September 1999
Lytic peptides HELIX BIOMEDIX, INC. 06 September 1994 19 January 1999
Ligand/lytic peptide compositions and methods of use BOARD OF SUPERVISORS OF LOUISIANA STATE UNIVERSITY AND AGRICULTURAL AND MECHANICAL COLLEGE 19 June 2009 21 January 2010
Methylated lysine-rich lytic peptides and method of making same by reductive alkylation DEMETER BIOTECHNOLOGIES, LTD. 24 April 1995 10 February 1998
Lytic peptides HELIX BIOMEDIX, INC. 15 January 1999 03 July 2001
See full citation <>

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