KR20140104288A - TNF-α INHIBITOR - Google Patents

Abstract

Disclosed are peptide with one sequence from among sequence number 1 to sequence number 161, fragment peptide of a sequence in the sequence number 1, or peptide having a sequence with the homogeny of 80% or greater to the peptide sequence; and a TNF-α inhibitor composition including the peptide as active ingredients. According to the present invention, the peptide with one sequence from among sequence number 1 to sequence number 161, the peptide having a sequence with the homogeny of 80% or greater to the peptide sequence, or the fragment peptide of one sequence has an excellent TNF-α inhibitor effect. Therefore, the composition including the peptide of the present invention is widely used to prevent and cure various diseases by being used as a medical composition or a food composition of curing or preventing TNF-α-mediated diseases.

Description

TNF-alpha inhibitor {TNF-alpha inhibitor}

The present invention relates to TNF alpha inhibitors and compositions comprising same.

Tumor necrosis factor (TNF), especially TNF-a, is released from inflammatory cells and is known to cause a variety of cytotoxic, immune and inflammatory responses. It has been known that TNF-a is involved in the development of many inflammatory diseases and autoimmune diseases and naturalization (prolongation), and when released into the blood to act on the whole body, it causes serious sepsis and septic shock. As described above, since TNF-a is a factor widely involved in the immune system of a living body, development of drugs that inhibit TNF-a has been actively carried out. TNF-α is biosynthesized in an inactive form and cleaved by a protease to become an active form. An enzyme involved in this activation is called a tumor necrosis factor-converting enzyme (TACE). Therefore, the substance that inhibits this TACE can treat, ameliorate, and prevent the diseases, condition, abnormal condition, and bad subjective symptoms caused by TNF-α (KR2011-0060940A).

Including but not limited to rheumatoid arthritis, psoriasis, eczema, Crohn's disease, chronic obstructive pulmonary disease (COPD), systemic lupus erythematosus (SLE), sepsis, endotoxic shock, multiple sclerosis and chronic hepatitis (J. Med. Chem., 42, 2295-2314, 1999; Am. J. Respir. Crit Care Med., 153, 633-637, 1996; Lupus, 11, 102-108, 2002; and Hepatogastroenterology., 47, 1675-1679, 2000).

In addition, TNF-α by the monoclonal antibody inhibition of TNF-α activity, or neutralization is seen in cases of infliximab (Remicade ^{TM) (infliximab (Remicade TM)} ) and control Daly mumaep (Humira ^{TM) (adalimumab (Humira TM)} ) As is the case, it has been found effective in treating immunological disorders including, but not limited to, rheumatoid arthritis, ankylosing spondylitis, Crohn's disease and psoriatic arthritis (Remicade ^™ (infliximab) prescribing information, Centocor, September 2005 ; HUMIRA ^TM (Adalimumap) prescription information, Abbott Laboratories, October 2005). Etanercept (Enbrel ^™ ) neutralizes the biological activity of TNF-α as a fusion protein with a decoy receptor part for TNF-α. Etanercept (Enbrel ^{TM) (etanercept (Enbrel TM)} ) has been prescribed for rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and psoriasis in the United States (Enbrel ^TM (etanercept) prescribing information, Immunex Corporation, July 2005).

Thus, while TNF-a inhibitors are recognized for their efficacy, widespread use is limited due to concerns about side effects.

KR2011-0060940A

J. Med. Chem., 42, 2295-2314, 1999; Am. J. Respir. Crit. Care Med., 153, 633-637, 1996; Lupus, 11, 102-108, 2002; Hepatogastroenterology., 47, 1675-1679, 2000.

Accordingly, the present inventors have made intensive efforts to develop a TNF-α inhibitor having an excellent effect while minimizing adverse effects, and have completed the present invention.

The present inventors have found that peptides derived from telomerase can have TNF-a inhibitory activity, and have completed the present invention.

Accordingly, an object of the present invention is to provide a peptide having TNF-a inhibitory activity.

It is another object of the present invention to provide a TNF-α inhibitory composition comprising a peptide having TNF-α inhibitory activity as an active ingredient.

It is another object of the present invention to provide a pharmaceutical composition comprising as an active ingredient a peptide having TNF-a inhibitory activity.

It is another object of the present invention to provide a food composition comprising a peptide having TNF-a inhibitory activity as an active ingredient.

According to one aspect of the present invention, there is provided a peptide having TNF alpha inhibitory activity, comprising a peptide comprising an amino acid sequence of any one of SEQ ID NOS: 1 to 161, a peptide having 80% or more sequence homology with the amino acid sequence, Peptides are provided.

According to another aspect of the present invention, the fragment may be a fragment composed of three or more amino acids.

According to another aspect of the present invention, the peptide may be composed of up to 30 amino acids.

According to another aspect of the present invention, the peptide may be an amino acid sequence of any one of SEQ ID NOS: 1 to 161.

According to another aspect of the present invention, the peptide may be an amino acid sequence comprising SEQ ID NO: 1.

According to another aspect of the present invention, there is provided a peptide according to any one of claims 1 to 6, 9, 11, 14 to 21, 23 to 43, 39, SEQ ID NO: 54, SEQ ID NO: 61, SEQ ID NO: 63 to SEQ ID NO: 82, SEQ ID NO: 84 to SEQ ID NO: 94, SEQ ID NO: 96, SEQ ID NO: 99 to SEQ ID NO: 104, SEQ ID NO: 107 to SEQ ID NO: SEQ ID NO: 115, SEQ ID NO: 116, SEQ ID NO: 120 to SEQ ID NO: 122, SEQ ID NO: 124, SEQ ID NO: 129 to SEQ ID NO: 133, SEQ ID NO: 142 to SEQ ID NO: 144, SEQ ID NO: 146, SEQ ID NO: 148, SEQ ID NO: SEQ ID NO: 155 to SEQ ID NO: 159.

According to another aspect of the present invention, the peptide is selected from the group consisting of SEQ ID NO: 15 to SEQ ID NO: 18, SEQ ID NO: 23 to SEQ ID NO: 27, SEQ ID NO: 29, SEQ ID NO: 31 to SEQ ID NO: 34, SEQ ID NO: 39 to SEQ ID NO: , SEQ ID NO: 48, SEQ ID NO: 51 to SEQ ID NO: 53, SEQ ID NO: 55 to SEQ ID NO: 58, SEQ ID NO: 61, SEQ ID NO: 65 to SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: SEQ ID NO: 84 to SEQ ID NO: 87, SEQ ID NO: 8 to 90, SEQ ID NO: 94, SEQ ID NO: 96, SEQ ID NO: 99, SEQ ID NO: 101 to SEQ ID NO: 104, SEQ ID NO: 107 to SEQ ID NO: 109, SEQ ID NO: An amino acid sequence selected from the group consisting of SEQ ID NO: 121, SEQ ID NO: 129 to SEQ ID NO: 132, SEQ ID NO: 142 to SEQ ID NO: 144, SEQ ID NO: 146, SEQ ID NO: 148, SEQ ID NO: 149, and SEQ ID NO: 157 to SEQ ID NO: . ≪ / RTI >

According to another aspect of the present invention, there is provided a peptide according to any one of claims 1 to 5, 7, 9, 10, 12, 13, 15, , SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 32 to SEQ ID NO: 53, SEQ ID NO: 55 to SEQ ID NO: 60, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72 to SEQ ID NO: SEQ ID NO: 94, SEQ ID NO: 99 to SEQ ID NO: 112, SEQ ID NO: 114, SEQ ID NO: 127 to SEQ ID NO: 144, SEQ ID NO: 146, SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 151 and SEQ ID NO: 153 to SEQ ID NO: And an amino acid sequence selected from the group consisting of SEQ ID NOs.

According to another aspect of the present invention, there is provided a peptide according to any one of claims 1 to 7, , SEQ ID NO: 25 to SEQ ID NO: 27, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 33 to SEQ ID NO: 43, SEQ ID NO: 156, SEQ ID NO: 157 and SEQ ID NO: 159 .

According to another aspect of the invention, the peptide may be derived from human telomerase.

According to one aspect of the present invention, there is provided a peptide having the TNF alpha inhibitory activity, comprising a peptide comprising the amino acid sequence of any one of SEQ ID NOs: 1 to 161 or a peptide having the sequence homology of 80% A polynucleotide encoding a peptide is provided.

According to another aspect of the invention, the peptide may be a polynucleotide encoding up to 30 amino acids.

According to another aspect of the present invention, the peptide may be a polynucleotide encoding a peptide consisting of an amino acid sequence of any one of SEQ ID NOs: 1-161.

According to another aspect of the present invention, the peptide may be a polynucleotide encoding a peptide that is derived from human telomerase.

According to one aspect of the present invention there is provided a pharmaceutical composition comprising a peptide comprising an amino acid sequence of any one of SEQ ID NOS: 1 to 161, a peptide having 80% or more sequence homology with the amino acid sequence, or a peptide thereof, An inhibiting composition is provided.

In another aspect of the present invention, the peptide may be composed of up to 30 amino acids.

The composition according to another aspect of the present invention may be one in which the peptide comprises the amino acid sequence of any one of SEQ ID NOS: 1 to 161.

A composition according to another aspect of the invention may be one in which the peptide is derived from human telomerase.

According to an aspect of the present invention, there is provided a peptide comprising an amino acid sequence of any one of SEQ ID NOS: 1 to 161, a peptide having 80% or more sequence homology with the amino acid sequence, or a peptide thereof, alpha inhibitory composition.

In a composition according to another aspect of the invention, the peptide may be composed of up to 30 amino acids.

In a composition according to another aspect of the present invention, the peptide may be composed of the amino acid sequence of any one of SEQ ID NOS: 1-116.

In a composition according to another aspect of the invention, the peptide may be derived from human telomerase.

In a composition according to another aspect of the present invention, the composition may be for the treatment or prevention of TNF-a mediated diseases.

In a composition according to another aspect of the present invention, the composition may be a pharmaceutical composition for the treatment or prevention of TNF-a mediated diseases.

In a composition according to another aspect of the present invention, the composition may be a food composition for the improvement or prevention of TNF-a mediated diseases.

In a composition according to another aspect of the present invention, the TNF-α mediated disease is selected from inflammatory bowel disease such as rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis, ulcerative colitis and Crohn's disease, ankylosing spondylitis, multiple sclerosis, (SLE), chronic obstructive pulmonary disease (COPD), sepsis, endotoxic shock, hepatitis, and type 1 diabetes.

According to one aspect of the present invention, there is provided a method of preventing or treating a TNF-α mediated disease, which comprises administering the above-mentioned composition.

According to an aspect of the present invention, there is provided a peptide comprising an amino acid sequence of any one of SEQ ID NOS: 1 to 161, a peptide having a sequence homology of 80% or more with the amino acid sequence, or a peptide or fragment thereof; And a kit for the prophylaxis or treatment of a TNF-α-mediated disease, which comprises an instruction that discloses at least one of a dose, an administration route, a frequency of administration, and indications of a peptide or a composition comprising the same.

A peptide having a sequence of any one of SEQ ID NOS: 1 to 161 according to the present invention, or a peptide having a sequence having a homology of 80% with the above sequence, or a fragment thereof, has an excellent TNF-a inhibitory effect. Accordingly, the composition comprising the peptide of the present invention can be used as a pharmaceutical composition or food composition for the prevention or treatment of TNF-a mediated diseases and thus can be widely used for the treatment and prevention of various diseases.

Figures 1 to 16 show the results of screening for the TNF-a inhibitory effect on monocytes.
FIGS. 17 to 35 show the results of screening for the TNF-.alpha. Inhibitory effect on the cell line THP-1.

The present invention can be variously modified and can have various embodiments, and the present invention will be described in more detail as follows. It is to be understood, however, that the invention is not to be limited to the specific embodiments, but includes all modifications, equivalents, and alternatives falling within the spirit and scope of the invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the present invention will be described in detail with reference to the accompanying drawings.

Reflecting the central role of TNF- [alpha] in inflammation and immune function, agents that inhibit the biological activity and production of TNF- [alpha] are inflammatory, And exhibits therapeutic effects in a variety of diseases such as bowel disease, ankylosing spondylitis, multiple sclerosis, systemic lupus erythematosus (SLE), chronic obstructive pulmonary disease (COPD), sepsis, endotoxic shock, hepatitis and type 1 diabetes. Some types of drugs are found to be more effective than other drugs depending on their mode of action and physicochemical properties. For example, PDE4 inhibitors such as roflumilast and cilomilast are being developed in large quantities for COPD. On the other hand, anti-TNF-alpha biologics have been prescribed for the first time in rheumatoid arthritis and have expanded their prescription coverage with ankylosing spondylitis, psoriasis and Crohn's disease. 5-Aminosalicylic acid and sulfasalazine are used in the treatment of mild inflammatory bowel disease, while steroids and anti-TNF- [alpha] biologics are prescribed severely. It has been attempted to treat inflammatory bowel disease using PDE4 inhibitors (Ann. Rev. Med. Chem., 38, 141-152, 2003). Although p38 inhibitors such as VX-702 have been evaluated for human rheumatoid arthritis, the therapeutic utility of MAP kinase inhibitors has not yet been identified (Curr. Opin. DrugDiscov. Devel., 8, 421-430, 2005) . Steroids are effective initially for a variety of immune diseases, but their long-term use is severely restricted due to side effects.

Telomere is a genetic material that is repeatedly present at the end of a chromosome, and is known to prevent damage to the chromosome or its binding to other chromosomes. As the cell divides, the length of the telomere is getting shorter. When there is more than a certain number of cell divisions, the telomere becomes very short, and the cell stops dividing and dies. On the other hand, it is known that lengthening the telomeres prolongs the life of the cells. For example, it is known that the cancer cells secrete an enzyme called telomerase and prevent the shortening of the telomeres. The present inventors have found that a number of peptides derived from telomerase can have TNF-a inhibitory activity and have completed the present invention.

One aspect of the present invention is a peptide having TNF alpha inhibitory activity, comprising a peptide comprising any one of the amino acid sequences of SEQ ID NOS: 1 to 161, a peptide having 80% or more sequence homology with the amino acid sequence, or a peptide to provide.

The peptides shown in SEQ ID NO: 1 to SEQ ID NO: 161 are shown in Table 1 below. SEQ ID NO: 180 is the sequence of human telomerase full-length protein. SEQ ID NO: 1 is a peptide derived from telomerase and consisting of 16 amino acids. The peptide of SEQ ID NO: 2 to SEQ ID NO: 77 is a peptide comprising the sequence of SEQ ID NO: The peptides of SEQ ID NO: 78 to SEQ ID NO: 161 are fragments of the peptide of SEQ ID NO: 1.

The "names" in Tables 1-4 below are named to distinguish the peptides. In another aspect of the present invention, at least one of the peptides of SEQ ID NO: 1 to SEQ ID NO: 161 includes a "synthetic peptide" synthesized by selecting peptides at corresponding positions among the peptides contained in telomerase. In the present specification, the term "pep" refers to a peptide having any one of SEQ ID NO: 1 to SEQ ID NO: 161, or a peptide having 80% or more of sequence homology with the sequence, or a fragment thereof.

[Table 1]

[Table 2]

[Table 3]

[Table 4]

An aspect of the present invention is a peptide having TNF alpha inhibitory activity, comprising a peptide comprising any one of the amino acid sequences of SEQ ID NOS: 1 to 161, a peptide having 80% or more of sequence homology with the amino acid sequence, or a peptide Encoding polynucleotides. Peptides can be mass produced using the polynucleotides. For example, a peptide containing a polynucleotide encoding a peptide can be cultured in a host cell by mass-production of the peptide.

The peptides disclosed herein may comprise peptides having greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99% sequence homology. Also, the peptide disclosed in the present specification can be prepared by reacting a peptide or a fragment thereof comprising SEQ ID NO: 1 with one or more amino acids, two or more amino acids, three or more amino acids, four or more amino acids, five or more amino acids, Or 7 or more amino acid altered peptides.

In one aspect of the invention, the amino acid change is of a property that causes the physicochemical properties of the peptide to change. For example, amino acid changes such as improving the thermal stability of the peptide, altering the substrate specificity, changing the optimum pH, etc. can be performed.

In one aspect of the present invention, a peptide comprising an amino acid sequence of any one of SEQ ID NOS: 1 to 161, a peptide having 80% or more sequence homology with the amino acid sequence, or a peptide thereof is a peptide comprising 30 or fewer amino acids .

In one aspect of the present invention, a peptide having the sequence of SEQ ID NOS: 1-161, a peptide of the sequence of SEQ ID NOS: 1-151, or a peptide having 80% or more of the sequence homology with the peptide sequence is a telomerase, And peptides derived from Homo sapiens telomerase.

As used herein, the term "amino acid" includes D-isomers and modified amino acids as well as the 22 standard amino acids that are naturally incorporated into the peptide. Accordingly, in one aspect of the present invention, the peptide may be a peptide comprising a D-amino acid. In another aspect of the present invention, the peptide may include post-translationally modified non-standard amino acids and the like. Examples of post-translational modifications include phosphorylation, glycosylation, acylation (including, for example, acetylation, myristoylation and palmitoylation), alkylation ), Carboxylation, hydroxylation, glycation, biotinylation, ubiquitinylation, changes in chemical properties (such as, for example, beta-depleted deamidation , Deamidation) and structural changes (e.g., formation of a disulfide bridge). Also included are amino acid changes such as changes in amino acids, such as changes in amino groups, carboxy groups or side chains, caused by chemical reactions that take place during binding with crosslinkers to form peptide conjugates.

The peptides disclosed herein may be wild type peptides identified and isolated from natural sources. Alternatively, the peptides disclosed herein may be artificial variants, including amino acid sequences in which one or more amino acids are substituted, deleted and / or inserted as compared to peptides that are fragments of SEQ ID NO: 1. Amino acid changes in wild-type polypeptides as well as in artificial variants include conservative amino acid substitutions that do not significantly affect folding and / or activity of the protein. Examples of conservative substitutions include, but are not limited to, basic amino acids (arginine, lysine and histidine), acidic amino acids (glutamic acid and aspartic acid), polar amino acids (glutamine and asparagine), hydrophobic amino acids (leucine, isoleucine, valine and methionine) Tryptophan and tyrosine), and small amino acids (glycine, alanine, serine and threonine). In general, amino acid substitutions that do not alter specific activity are known in the art. The most commonly occurring interactions are Ala / Ser, Val / Ile, Asp / Glu, Thr / Ser, Ala / Gly, Ala / Thr, Ser / Asn, Ala / Val, Ser / Gly, Tyr / Lys / Arg, Asp / Asn, Leu / Ile, Leu / Val, Ala / Glu, and Asp / Gly, and vice versa. Other examples of conservative substitutions are shown in the following table.

[Table 5]

Substantial variations in the biological properties of the peptide include (a) the structure of the polypeptide backbone within the substitution region, e.g., their effect in maintaining the sheet or helical conformation, (b) the charge of the molecule at the target site Or their effect in maintaining hydrophobicity, or (c) their effect in maintaining the bulk of the side chain is significantly different. The natural residues are grouped into the following groups based on their usual side chain properties:

(1) hydrophobicity: norleucine, met, ala, val, leu, ile;

(2) Neutral hydrophilic: cys, ser, thr;

(3) Acid: asp, glu;

(4) Basicity: asn, gln, his, lys, arg;

(5) Residues affecting chain orientation: gly, pro; And

(6) Aromatic: trp, tyr, phe.

Non-conservative substitutions will be made by exchanging one member of these members for another. Any cysteine residue not associated with maintaining the proper stereostructure of the peptide can generally be replaced with a serine to enhance the oxidative stability of the molecule and prevent strange cross-linking. Conversely, cysteine bond (s) can be added to the peptide to improve its stability

Other types of amino acid variants of peptides are those in which the glycosylation pattern of the antibody is altered. The term change refers to the deletion of one or more carbohydrate moieties found in the peptide and / or the addition of one or more glycosylation sites that are not present in the peptide.

Glycosylation of peptides is typically N-linked or O-linked. N-linked refers to a carbohydrate moiety attached to the side chain of an asparagine moiety. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine (where X is any amino acid except proline) are recognition sequences for enzymatically attaching carbohydrate moieties to asparagine side chains. Thus, the presence of one of these tripeptide sequences in the polypeptide creates a potential glycosylation site. O-linked glycosylation refers to attaching one of the sugars N-acetylgalactosamine, galactose or xylose to a hydroxyamino acid, most commonly serine or threonine, but 5-hydroxyproline or 5-hydroxylysine May be used.

Addition of the glycosylation site to the peptide is conveniently accomplished by varying the amino acid sequence to contain one or more of the above-mentioned tripeptide sequences (in the case of N-linked glycosylation sites). Such changes may be made by adding one or more serine or threonine residues to the sequence of the original antibody or by substituting these residues (for O-linked glycosylation sites).

In one aspect of the invention, the polynucleotide can be a naturally occurring or artificial DNA or RNA molecule as the nucleic acid molecule, and can be single-stranded or double-stranded. The nucleic acid molecule may be one or more, it may be a nucleic acid molecule of the same type (e.g. having the same nucleotide sequence), or it may be a nucleic acid molecule of another type. But are not limited to, DNA, cDNA, decoy DNA, RNA, siRNA, miRNA, shRNA, stRNA, snoRNA, snRNA, PNA, antisense oligomer, plasmid and other modified nucleic acids It is not.

Also, a peptide comprising an amino acid sequence of any one of SEQ ID NOS: 1 to 161 according to an aspect of the present invention, a peptide having 80% or more sequence homology with the amino acid sequence, or a peptide thereof is low in intracellular toxicity, And has a high stability.

In one aspect of the present invention, there is provided a pharmaceutical composition comprising a peptide comprising an amino acid sequence of any one of SEQ ID NOS: 1 to 161, a TNF-α inhibitor comprising a peptide having 80% or more sequence homology with the amino acid sequence, Lt; / RTI >

The TNF-α inhibitory composition according to one aspect of the present invention comprises, in one aspect, a peptide comprising an amino acid sequence of any one of SEQ ID NOS: 1-161, a peptide having 80% or more sequence homology with the amino acid sequence, May be contained in an amount of 0.1 μg / mg to 1 mg / mg, specifically 1 μg / mg to 0.5 mg / mg, more specifically, 10 μg / mg to 0.1 mg / mg. When it is included in the above range, it is not only suitable for exhibiting the intended effect of the present invention but also can satisfy both the stability and safety of the composition, and may be suitably included in the above range in terms of cost effectiveness.

The composition according to one aspect of the present invention can be applied to all animals including humans, dogs, chickens, pigs, cattle, sheep, guinea pigs or monkeys.

In one aspect of the present invention, the composition comprises a peptide having a sequence selected from the group consisting of SEQ ID NOS: 1 to 161, a peptide having a sequence of SEQ ID NO: 1, or a peptide having a sequence homology of 80% A medicament for treating or preventing TNF-a mediated diseases. The pharmaceutical composition according to one aspect of the present invention can be administered orally, rectally, transdermally, intravenously, intramuscularly, intraperitoneally, intramuscularly, intradermally or subcutaneously.

Formulations for oral administration may be, but are not limited to, tablets, pills, soft or hard capsules, granules, powders, solutions or emulsions. Formulations for parenteral administration may be, but are not limited to, injections, drops, lozenges, ointments, gels, creams, suspensions, emulsions, suppositories, patches or spraying agents.

The pharmaceutical composition according to one aspect of the present invention may contain additives such as a diluent, an excipient, a lubricant, a binder, a disintegrant, a buffer, a dispersant, a surfactant, a colorant, a fragrance or a sweetener as necessary. The pharmaceutical composition according to one aspect of the present invention can be prepared by a conventional method in the art.

The effective ingredients of the pharmaceutical composition according to one aspect of the present invention will vary depending on the age, sex, weight, pathological condition and severity of the subject to be administered, route of administration, or judgment of the prescriber. Determination of the amount of application based on these factors is within the level of ordinary skill in the art and its daily dose is, for example, from 0.1 [mu] g / kg / day to 1 g / kg / day, Kg / day, more specifically, 10 μg / kg / day to 1 mg / kg / day, and more particularly 50 μg / kg / day to 100 μg / kg / day. The pharmaceutical composition according to one aspect of the present invention may be administered once to three times a day, but is not limited thereto.

In one aspect of the present invention, the composition comprises a peptide having a sequence selected from the group consisting of SEQ ID NOS: 1 to 161, a peptide having a sequence of SEQ ID NO: 1, or a peptide having a sequence homology of 80% And a food composition for preventing or inhibiting TNF-α mediated diseases.

The formulation of the food composition according to one aspect of the present invention is not particularly limited, but can be formulated into, for example, tablets, granules, powders, liquids, solid preparations and the like. Each formulation may be blended without difficulty by a person skilled in the art according to the purpose of formulation or use, in addition to the active ingredient, and the synergistic effect may occur when the composition is applied simultaneously with other ingredients.

Determination of the dosage of the active ingredient is within the level of ordinary skill in the art and its daily dose is, for example, 1 μg / kg / day to 10 mg / kg / day, more specifically 10 μg / kg / day Day to 100 mg / kg / day, but it is not limited thereto, and it may be various factors such as the age, health condition, and complication of the subject to be administered ≪ / RTI >

One aspect of the present invention relates to a peptide comprising an amino acid sequence of any one of SEQ ID NOS: 1 to 161, a peptide having a sequence homology of 80% or more with the amino acid sequence, or a peptide fragment thereof, for the prevention or treatment of TNF- Lt; / RTI >

A peptide comprising an amino acid sequence of any one of SEQ ID NOS: 1 to 161 of the present invention, a peptide having a sequence homology of 80% or more with the amino acid sequence, or a peptide thereof or a composition comprising the same, The present invention provides a method for preventing or treating a TNF-a mediated disease of a subject.

In one aspect of the present invention, the composition comprises a peptide comprising an amino acid sequence of any one of SEQ ID NOS: 1 to 161, a peptide having a sequence homology of 80% or more with the amino acid sequence, or a peptide or fragment thereof; And a kit for the prophylaxis or treatment of TNF-α mediated diseases, which comprises an instruction that discloses at least one of the dose, administration route, number of doses and indications of the peptide or composition comprising the same.

The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The abbreviated term in front of a noun is not intended to limit the quantity but to indicate that there is more than one noun item mentioned. The terms " comprising ", "having ", and" containing "are to be construed as open (i.e., meaning including but not limited to).

It is important to note that the reference to a range of values is an easy way to substitute for referring individually to each distinct value within the range, and unless otherwise specified, each separate value is referred to individually Which is incorporated herein by reference. All range end values are contained within that range and can be combined independently.

All methods mentioned herein may be performed in any suitable order unless otherwise indicated or clearly contradicted by context. It is to be understood that the use of any embodiment and all of the embodiments or example language (e.g., "such as ") is for the purpose of describing the present invention only, It is not intended to be limiting. No language in the specification should be construed as obliging any non-claimed components to practice the present invention. Unless defined otherwise, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

Preferred embodiments of the present invention include the most optimal mode known to the inventors for carrying out the present invention. Variations of the preferred embodiments may become apparent to those skilled in the art upon reading the foregoing description. The inventors expect those skilled in the art to appropriately utilize such variations, and the inventors expect the invention to be practiced otherwise than as described herein. Accordingly, the present invention includes equivalents and all modifications of the subject matter of the invention as recited in the appended claims, as permitted by the patent law. Moreover, any combination of the above-mentioned components within all possible variations is included in the present invention unless otherwise specified or contradicted by context. While the present invention has been particularly shown and described with reference to exemplary embodiments, those skilled in the art will readily appreciate that various changes in form and detail may be made without departing from the spirit and scope of the invention as defined by the following claims .

Hereinafter, the constitution and effects of the present invention will be described in more detail with reference to Examples and Experimental Examples. However, the following examples and experimental examples are provided for illustrative purposes only in order to facilitate understanding of the present invention, and the scope and scope of the present invention are not limited thereto.

Example 1: Synthesis of PEP 1 (SEQ ID NO: 1) and measurement of TNF alpha inhibition

Experimental Example 1: Synthesis of PEP 1 (SEQ ID NO: 1)

A peptide composed of 16 amino acids having the structural formula of the following formula (1) was synthesized as a peptide (PEP 1) of SEQ ID NO: 163 selected from human telomerase.

SEQ ID NO: 163: EARPALLTSRLRFIPK

≪ Formula 1 >

The peptide PEP 1 of SEQ ID NO: 163 can be produced according to a conventional solid phase peptide synthesis method. Specifically, the peptides were synthesized by coupling one amino acid from the C-terminal through Fmoc solid phase peptide synthesis (SPPS) using ASP48S (Peptron, Inc., Daejeon, Korea). The first amino acid at the C-terminus of the peptides attached to the resin was used as follows. For example:

NH ₂ -Lys (Boc) -2-chloro-Trityl Resin

NH ₂ -Ala-2-chloro-Trityl Resin

NH ₂ -Arg (Pbf) -2-chloro-Trityl Resin

All amino acid sources used for peptide synthesis are Trt, Boc, t-Bu (t-butylester), Pbf (2,2,4,6, 7-pentamethyl dihydro-benzofuran-5-sulfonyl). For example:

Fmoc-Pro-OH, Fmoc-Leu-OH, Fmoc-Phe-OH, Fmoc-Phe-OH, Fmoc-Arg- Fmoc-Lys (Boc) -OH, Fmoc-Gln (Trt) -OH, Fmoc-Trp (Boc) -OH, Fmoc-Met-OH, Fmoc- -Asn (Trt) -OH, Fmoc-Tyr (tBu) -OH, Fmoc-Ahx-OH, Trt-Mercaptoacetic acid.

As the coupling reagent, HBTU [2- (1H-Benzotriazole-1-yl) -1,1,3,3-tetramethylaminium hexafluorophosphate] / HOBt [N-Hydroxxybenzotriazole] / NMM [4-Methylmorpholine] Respectively. Fmoc removal was performed using piperidine in DMF in 20% DMF. Cleavage Cocktail (TFA (trifluoroacetic acid) / TIS (triisopropylsilane) / EDT (ethanedithiol) / H ₂ O = 92.5 / 2.5 / 2.5 / 2.5] was used to remove the synthetic peptides from the resin and to remove the protecting groups of the residues. Respectively.

Each of the peptides was synthesized by repeating the steps of reacting corresponding amino acids with a starting amino acid having an amino acid protecting group bonded thereto on a solid support, washing with a solvent, followed by deprotection. The synthesized peptide was cleaved from the resin and purified by HPLC. The synthesis was confirmed by MS and lyophilized.

The detailed synthesis procedure of PEP 1 will be described as follows.

1) Coupling

The protected amino acid (8 eq) and the coupling reagent HBTU (8 eq) / HOBt (8 eq) / NMM (16 eq) were dissolved in DMF and added to NH ₂ -Lys (Boc) -2-chloro-Trityl Resin , And reacted at room temperature for 2 hours and washed with DMF, MeOH and DMF in that order.

2) Fmoc deprotection

Piperidine in DMF in 20% DMF was added, and the reaction was carried out at room temperature for 5 minutes twice, followed by washing with DMF, MeOH and DMF.

3) By the reaction of 1 and 2 repeatedly peptide basic skeleton _{NH 2 -E (OtBu) -AR (} Pbf) -PALLT (tBu) -S (tBu) -R (Pbf) LR (Pbf) -FIPK (Boc) -2-chloro-Trityl Resin).

4) Cleavage: Cleavage cocktail was added to the synthesized peptide Resin to separate the peptide from the resin.

5) Cooling diethyl ether is added to the obtained mixture, and the resulting peptide is precipitated by centrifugation.

6) After purification by Prep-HPLC, the molecular weight was confirmed by LC / MS and frozen to prepare powder.

Experimental Example 2: Effect of PEP 1 on inhibition of TNF alpha in liver cancer cell line

Experimental Example 2-1: Cell culture

Blood was collected from healthy individuals (50 ml) and PBMC (peripheral blood mononuclear cell) layer was recovered using Ficoll-Paque PLUS (GE Healthcare Life Sciences, Piscataway, NJ, USA). The recovered PBMC were suspended in RPMI 1640 medium (Invitrogen / Life Technologies, Carlsbad, Calif., USA) supplemented with human serum (20%) and cultured in 100-mm polystyrene cell culture Plate and incubated for 2 hours at 37 ° C in a 5% incubator for 2 hours. Then RPMI 1640 medium so that the per well 1 × 10 ⁵ cells in 96-well plates After removing the monocytes (monocytes) attached to the floor with cold PBS (Phosphate Buffered Saline) (Gibco / Life Technologies, Carlsbad, CA, USA) ( 100 mg / ml, human serum; 20%) supplemented with penicillin-streptomycin;

In addition, HEK293 (human embryonic kidney 293) cell line (HEK293 / TLR2) and normal HEK293 (HEK293 / null) cell line, which are stably expressing TLR2 (toll-like receptor 2), were purchased from the Seoul National University Dental Graduate School and luciferase Were used for analysis. HEK293 / null and HEK293 / TLR2 cell line Luciferase Assay to 2.5 × 10 ⁵ cells DMEM (Dulbecco's modified Eagle's medium ) such that per well in 12-well plates the day before the medium (supplemented with blasticidin; 10 μg / ml, fetal bovine serum ; 10%) (Invitrogen / Life Technologies, Carlsbad, Calif., USA).

Experimental Example 2-2: Cytokine assay

To investigate the effect of PEP 1, an enzyme-linked immunosorbent assay (ELISA) was performed on TNF-α. PBMC-derived monocytes were cultured in a 96 well plate one day prior to the experiment to be 1 x 105 cells per well. LPS (lipopolysaccharide; 10 ng / ml, Sigma) was then treated for 2 hours and washed three times with PBS. (FITC), FITC-TAT, PEP 1-FITC, and FITC-PEP 1 after starvation for 1 hour with OPTI-MEM medium (Invitrogen / Life Technologies, Carlsbad, CA, USA) 4 μM and cultured for 2 hours. After the incubation, the cell culture medium was removed and TNF-α was quantified according to ELISA kit (R & D, Minneapolis, MN, USA).

TNF measurement is performed by sandwich ELISA. Add 100 ul of TNFα primary antibody to precoated 96 well plate and overnight at 4 ° C. The next day, wash with 0.5% tween 20 wash solution three times for 5 minutes, then add 100 μl of sample to be measured and standard solution, and react at room temperature for 2 hours. After washing as above, 100 μl of HRP-conjugated secondary antibody is added and reacted at room temperature for 2 hours. Then wash again and add avidin / biotin to measure the absorbance. The standard curve is obtained from the absorbance of the standard and the amount of TNF? Is quantitated from the absorbance of each sample.

PBMC-derived monocytes were stimulated with endotoxin LPS (10 ng / ml) for 2 hours, starved with OPTI-MEM for 1 hour and then streaked with FITC, FITC-TAT, PEP 1-FITC, and FITC -PEP 1 was reacted at a concentration of 4 μμ for 2 hours. The levels of TNF-α in the cell culture medium after the reaction were measured by ELISA. As a result, FITC and FITC-TAT showed higher levels of TNF-α due to LPS (6.2 and 6.7 ng / 1 showed a significant decrease in TNF-α levels (0.17 and 0.25 ng / ml) and the difference was statistically significant (P <0.01).

Example 2: PEP series (SEQ ID NO: 1 to SEQ ID NO: 161) Peptide TNF- α inhibition activity measurement

An inhibitory activity against the peptide of SEQ ID NO: 163 (PEP 1) was confirmed in Example 1, and on the basis of this, an experiment for confirming the TNF-α inhibitory activity against peptides of SEQ ID NOS: 1 to 161 Respectively. The peptide of SEQ ID NO: 1 to SEQ ID NO: 161 was synthesized by using the same method as that for synthesizing PEP 1 of SEQ ID NO: 163 described in Example 1, except that the amino acids to be attached were different.

Experimental Example 1: Cell culture

Blood was collected from healthy subjects (50 ml) and the PBMC (peripheral blood mononuclear cells) layer was recovered using a Biocoll Separating Solution (Biochrom AG, Berlin, Germany). The recovered PBMCs were suspended in RPMI 1640 medium supplemented with human serum (20%) and transferred to a 100-mm polystyrene cell culture plate coated with human serum for about 30 minutes. The cells were incubated for 2 hours at 37 ° C in a 5% For 2 hours. Then After removing the monocytes (monocytes) attached to the floor with cold PBS 96-well plate (well plate) 1 × 10 ⁵ cells to RPMI 1640 medium (supplemented with penicillin-streptomycin per well in; 100 mg / ml, human serum; 20%) and incubated the day before the experiment.

Experimental Example 2: Analysis of TNF-a inhibitory activity

ELISA experiments were performed to determine the effect of the peptides of the PEP series on TNF-a. Experiments to be 1 × 10 ⁵ cells per well of the monocytes (monocytes) resulting in a 96-well plate in PBMC incubated before day. LPS (lipopolysaccharide; 10 ng / ml, Sigma) is then treated for 2 hours and washed three times with PBS. Put OPTI-MEM medium in starvation for 1 hour, then treat the peptides with 4 μM and incubate for 2 hours. Cells treated with LPS (10 ng / ml) or with LPS (10 ng / ml) were treated with estrogen (20 nM) or cells treated with estrogen (20 nM as a kind of estrogen) (20 nM) were used as the control group. In addition, TNF-a inhibitory activity of PEP 1, which was confirmed in Example 1 as a control, was also measured. After incubation, the cell culture medium was removed and TNF-α was quantitated according to ELISA kit (R & D, Minneapolis, MN, USA). The specific quantitative method is as described in Experimental Example 2-2 of Example 1 .

Through the above experiment Peptides that affect the level of TNF-a were screened. Monocytes derived from PBMCs were stimulated with endotoxin LPS (10 ng / ml) for 2 hours and put on starvation with OPTI-MEM for 1 hour. Then, 161 peptides were incubated at 4 μM for 2 hours Lt; / RTI &gt; After the reaction, the levels of TNF-a in the cell culture were measured by ELISA and peptides that decreased the level of TNF- alpha compared to the control or PEP 1 were screened (Figs. 1 to 16).

SEQ ID NO: 1 to SEQ ID NO: 6, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 14 to 21, SEQ ID NO: 23 to SEQ ID NO: 37, SEQ ID NO: 39 to SEQ ID NO: 44, SEQ ID NO 47 to SEQ ID NO: 53, SEQ ID NO 55 to SEQ ID NO 61, SEQ ID NO 63 to SEQ ID NO 82, SEQ ID NO 84 to SEQ ID NO 94, SEQ ID NO 96, SEQ ID NO 99 to SEQ ID NO 104, SEQ ID NO: 107 to SEQ ID NO: 109, SEQ ID NO: 115, SEQ ID NO: 116, SEQ ID NO: 120 to SEQ ID NO: 122, SEQ ID NO: 124, SEQ ID NO: 129 to SEQ ID NO: 133, SEQ ID NO: 142 to SEQ ID NO: 144, SEQ ID NO: 148, SEQ ID NO: 149 and SEQ ID NO: 155 to SEQ ID NO: 159 were selected.

SEQ ID NO: 15 to SEQ ID NO: 18, SEQ ID NO: 23 to SEQ ID NO: 27, SEQ ID NO: 29, SEQ ID NO: 31 to SEQ ID NO: 34, SEQ ID NO: 39 to SEQ ID NO: 39 as a peptide for decreasing the expression amount of TNF- SEQ ID NO: 41, SEQ ID NO: 47, SEQ ID NO: 51 to SEQ ID NO: 53, SEQ ID NO: 55 to SEQ ID NO: 58, SEQ ID NO: 61, SEQ ID NO: 65 to SEQ ID NO: 68, SEQ ID NO: , SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 84 to SEQ ID NO: 87, SEQ ID NO: 8 = 90 to SEQ ID NO: 94, SEQ ID NO: 96, SEQ ID NO: 99, SEQ ID NO: 101 to SEQ ID NO: 104, SEQ ID NO: 107 to SEQ ID NO: The peptides of SEQ ID NO: 120, SEQ ID NO: 121, SEQ ID NO: 129 to SEQ ID NO: 132, SEQ ID NO: 142 to SEQ ID NO: 144, SEQ ID NO: 146, SEQ ID NO: 148, SEQ ID NO: 149 and SEQ ID NO: 157 to SEQ ID NO: .

Experimental Example 3: Peptide reanalysis affecting the level of TNF- ? In the THP1 cell line

Experiments were performed using human acute monocytic leukemia cell line THP-1 cells ( American Type Culture Collection (ATCC), Manassas, VA, USA). The THP-1 was a 96-well plate such that a 1 × 10 ⁵ cells per well suspended in RPMI 1640 medium and incubated for 24 hours. At this time, PMA (phorbol 12-myristate 13-acetate) was treated with 100 nM for differentiation into macrophages.

The cell line, THP-1, was differentiated into PMA and tested to confirm the results. The THP-1 cell line that was stimulated with PMA for one day was treated with LPS for 2 hours, followed by 1 hour starvation treatment and PEP 1 hour treatment.

The THP-1 cell line differentiated with PMA was stimulated with endotoxin LPS (10 ng / ml) for 2 hours, washed twice with PBS, and starved with OPTI-MEM for 1 hour to obtain 161 peptides in 1 μM Concentration for 1 hour. After the reaction, the levels of TNF-a in the cell culture medium were measured by ELISA and peptides that decreased the level of TNF- alpha were cleared compared to the comparison group (Fig. 17 to Fig. 35).

As a result of screening of peptides, the peptides which decrease the level of TNF-? As compared with the comparison group treated with LPS alone are shown as SEQ ID NO: 1 to SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17 to SEQ ID NO: 27, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 32 to SEQ ID NO: 53, SEQ ID NO: 55 to SEQ ID NO: 60, SEQ ID NO: 67, SEQ ID NO: SEQ ID NO: 72 to SEQ ID NO: 82, SEQ ID NO: 84 to SEQ ID NO: 92, SEQ ID NO: 94, SEQ ID NO: 99 to SEQ ID NO: 112, SEQ ID NO: 114, SEQ ID NO: 127 to SEQ ID NO: 144, SEQ ID NO: 146, SEQ ID NO: 148, 149, SEQ ID NO: 151 and SEQ ID NO: 153 to SEQ ID NO: 161 were selected.

Also, as peptides for decreasing the expression amount of TNF-? Compared to LPS + estrogen, the peptides of SEQ ID NO: 1 to SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: Peptides of SEQ ID NO: 17 to SEQ ID NO: 23, SEQ ID NO: 25 to SEQ ID NO: 27, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 33 to SEQ ID NO: 43, SEQ ID NO: 156, SEQ ID NO: 157 and SEQ ID NO:

&Lt; 110 > KAEL-GemVax Co., Ltd.          KIM, Sangjae <120> TNF-alpha inhibitor <130> 13p090ind <160> 163 <170> PatentIn version 3.2 <210> 1 <211> 30 <212> PRT <213> Homo sapiens <400> 1 Ala Leu Phe Ser Val Leu Asn Tyr Glu Arg Ala Arg Arg Pro Gly Leu   1 5 10 15 Leu Gly Ala Ser Val Leu Gly Leu Asp Asp Ile His Arg Ala              20 25 30 <210> 2 <211> 15 <212> PRT <213> Homo sapiens <400> 2 Ser Val Leu Asn Tyr Glu Arg Ala Arg Arg Pro Gly Leu Leu Gly   1 5 10 15 <210> 3 <211> 10 <212> PRT <213> Homo sapiens <400> 3 Gly Leu Leu Gly   1 5 10 <210> 4 <211> 10 <212> PRT <213> Homo sapiens <400> 4 Ala Leu Leu Thr Ser Arg Leu Arg Phe Ile   1 5 10 <210> 5 <211> 9 <212> PRT <213> Homo sapiens <400> 5 Arg Pro Ala Leu Leu Thr Ser Arg Leu   1 5 <210> 6 <211> 9 <212> PRT <213> Homo sapiens <400> 6 Arg Leu Thr Ser Arg Val Lys Ala Leu   1 5 <210> 7 <211> 15 <212> PRT <213> Homo sapiens <400> 7 Arg Thr Phe Val Leu Arg Val Arg Ala Gln Asp Pro Pro Pro Glu   1 5 10 15 <210> 8 <211> 15 <212> PRT <213> Homo sapiens <400> 8 Arg Leu Thr Ser Arg Val Lys Ala Leu Phe Ser Val Leu Asn Tyr   1 5 10 15 <210> 9 <211> 15 <212> PRT <213> Homo sapiens <400> 9 Ala Glu Arg Leu Thr Ser Arg Val Lys Ala Leu Phe Ser Val Leu   1 5 10 15 <210> 10 <211> 9 <212> PRT <213> Homo sapiens <400> 10 Tyr Glu Arg Ala Arg Arg Pro Gly Leu   1 5 <210> 11 <211> 9 <212> PRT <213> Homo sapiens <400> 11 Leu Leu Gly   1 5 <210> 12 <211> 10 <212> PRT <213> Homo sapiens <400> 12 Val Leu Gly Leu Asp Asp Ile His Arg Ala   1 5 10 <210> 13 <211> 10 <212> PRT <213> Homo sapiens <400> 13 Gly Ala Ser Val Leu Gly Leu Asp Asp Ile   1 5 10 <210> 14 <211> 10 <212> PRT <213> Homo sapiens <400> 14 Ala Leu Phe Ser Val Leu Asn Tyr Glu Arg   1 5 10 <210> 15 <211> 10 <212> PRT <213> Homo sapiens <400> 15 Ser Val Leu Asn Tyr Glu Arg Ala Arg Arg   1 5 10 <210> 16 <211> 10 <212> PRT <213> Homo sapiens <400> 16 Ser Val Leu Gly Leu Asp Asp Ile His Arg   1 5 10 <210> 17 <211> 10 <212> PRT <213> Homo sapiens <400> 17 Phe Ser Val Leu Asn Tyr Glu Arg Ala Arg   1 5 10 <210> 18 <211> 10 <212> PRT <213> Homo sapiens <400> 18 Asn Tyr Glu Arg Ala Arg Arg Pro Gly Leu   1 5 10 <210> 19 <211> 10 <212> PRT <213> Homo sapiens <400> 19 Tyr Glu Arg Ala Arg Arg Pro Gly Leu Leu   1 5 10 <210> 20 <211> 10 <212> PRT <213> Homo sapiens <400> 20 Arg Pro Gly Leu Leu Gly Ala Ser Val Leu   1 5 10 <210> 21 <211> 9 <212> PRT <213> Homo sapiens <400> 21 Glu Arg Ala Arg Arg Pro Gly Leu Leu   1 5 <210> 22 <211> 9 <212> PRT <213> Homo sapiens <400> 22 Val Leu Gly Leu Asp Asp Ile His Arg   1 5 <210> 23 <211> 9 <212> PRT <213> Homo sapiens <400> 23 Ser Val Leu Asn Tyr Glu Arg Ala Arg   1 5 <210> 24 <211> 9 <212> PRT <213> Homo sapiens <400> 24 Val Leu Asn Tyr Glu Arg Ala Arg Arg   1 5 <210> 25 <211> 9 <212> PRT <213> Homo sapiens <400> 25 Ala Arg Arg Pro Gly Leu Leu Gly Ala   1 5 <210> 26 <211> 9 <212> PRT <213> Homo sapiens <400> 26 Pro Gly Leu Leu Gly Ala Ser Val Leu   1 5 <210> 27 <211> 9 <212> PRT <213> Homo sapiens <400> 27 Arg Arg Pro Gly Leu Leu Gly Ala Ser   1 5 <210> 28 <211> 9 <212> PRT <213> Homo sapiens <400> 28 Ala Leu Phe Ser Val Leu Asn Tyr Glu   1 5 <210> 29 <211> 9 <212> PRT <213> Homo sapiens <400> 29 Gly Leu Leu Gly   1 5 <210> 30 <211> 9 <212> PRT <213> Homo sapiens <400> 30 Ser Val Leu Gly Leu Asp Asp Ile His   1 5 <210> 31 <211> 8 <212> PRT <213> Homo sapiens <400> 31 Glu Arg Ala Arg Arg Pro Gly Leu   1 5 <210> 32 <211> 8 <212> PRT <213> Homo sapiens <400> 32 Ala Arg Arg Pro Gly Leu Leu Gly   1 5 <210> 33 <211> 8 <212> PRT <213> Homo sapiens <400> 33 Gly Leu Leu Gly Ala Ser Val Leu   1 5 <210> 34 <211> 8 <212> PRT <213> Homo sapiens <400> 34 Arg Ala Arg Arg Pro Gly Leu Leu   1 5 <210> 35 <211> 8 <212> PRT <213> Homo sapiens <400> 35 Leu Gly Ala Ser Val Leu Gly Leu   1 5 <210> 36 <211> 15 <212> PRT <213> Homo sapiens <400> 36 Val Thr Glu Thr Thr Phe Gln Lys Asn Arg Leu Phe Phe Tyr Arg   1 5 10 15 <210> 37 <211> 15 <212> PRT <213> Homo sapiens <400> 37 Leu Phe Phe Tyr Arg Lys Ser Val Trp Ser Lys Leu Gln Ser Ile   1 5 10 15 <210> 38 <211> 15 <212> PRT <213> Homo sapiens <400> 38 Lys Leu Gln Ser Ile Gly Ile Arg Gln His Leu Lys Arg Val Gln   1 5 10 15 <210> 39 <211> 15 <212> PRT <213> Homo sapiens <400> 39 Glu Ala Glu Val Arg Gln His Arg Glu Ala Arg Pro Ala Leu Leu   1 5 10 15 <210> 40 <211> 15 <212> PRT <213> Homo sapiens <400> 40 Arg Pro Ala Leu Leu Thr Ser Arg Leu Arg Phe Ile Pro Lys Pro   1 5 10 15 <210> 41 <211> 15 <212> PRT <213> Homo sapiens <400> 41 Phe Ile Pro Lys Pro Asp Gly Leu Arg Pro Ile Val Asn Met Asp   1 5 10 15 <210> 42 <211> 15 <212> PRT <213> Homo sapiens <400> 42 Arg Thr Phe Arg Arg Glu Lys Arg Ala Glu Arg Leu Thr Ser Arg   1 5 10 15 <210> 43 <211> 15 <212> PRT <213> Homo sapiens <400> 43 Leu Asp Asp Ile His Arg Ala Trp Arg Thr Phe Val Leu Arg Val   1 5 10 15 <210> 44 <211> 15 <212> PRT <213> Homo sapiens <400> 44 Phe Val Leu Arg Val Ala Gln Asp Pro Pro Pro Glu Leu Tyr   1 5 10 15 <210> 45 <211> 15 <212> PRT <213> Homo sapiens <400> 45 Pro Gln Asp Arg Leu Thr Glu Val Ile Ala Ser Ile Ile Lys Pro   1 5 10 15 <210> 46 <211> 15 <212> PRT <213> Homo sapiens <400> 46 Lys Ser Val Trp Ser Lys Leu Gln Ser Ile Gly Ile Arg Gln His   1 5 10 15 <210> 47 <211> 16 <212> PRT <213> Homo sapiens <400> 47 Leu Lys Arg Val Gln Leu Arg Glu Leu Ser Glu Ala Glu Val Arg Gln   1 5 10 15 <210> 48 <211> 20 <212> PRT <213> Homo sapiens <400> 48 Met Pro Arg Ala Pro Arg Cys Arg Ala Val Arg Ser Leu Leu Arg Ser   1 5 10 15 His Tyr Arg Glu              20 <210> 49 <211> 20 <212> PRT <213> Homo sapiens <400> 49 Val Leu Pro Leu Ala Thr Phe Val Arg Arg Leu Gly Pro Gln Gly Trp   1 5 10 15 Arg Leu Val Gln              20 <210> 50 <211> 20 <212> PRT <213> Homo sapiens <400> 50 Arg Gly Asp Pro Ala Ala Phe Arg Ala Leu Val Ala Gln Cys Leu Val   1 5 10 15 Cys Val Pro Trp              20 <210> 51 <211> 20 <212> PRT <213> Homo sapiens <400> 51 Asp Ala Arg Pro Pro Pro Ala Ala Pro Ser Phe Arg Gln Val Ser Cys   1 5 10 15 Leu Lys Glu Leu              20 <210> 52 <211> 20 <212> PRT <213> Homo sapiens <400> 52 Val Ala Arg Val Leu Gln Arg Leu Cys Glu Arg Gly Ala Lys Asn Val   1 5 10 15 Leu Ala Phe Gly              20 <210> 53 <211> 20 <212> PRT <213> Homo sapiens <400> 53 Phe Ala Leu Leu Asp Gly Ala Arg Gly Gly Pro Pro Glu Ala Phe Thr   1 5 10 15 Thr Ser Val Arg              20 <210> 54 <211> 20 <212> PRT <213> Homo sapiens <400> 54 Ser Tyr Leu Pro Asn Thr Val Thr Asp Ala Leu Arg Gly Ser Gly Ala   1 5 10 15 Trp Gly Leu Leu              20 <210> 55 <211> 20 <212> PRT <213> Homo sapiens <400> 55 Leu Arg Arg Val Gly Asp Asp Val Leu Val His Leu Leu Ala Arg Cys   1 5 10 15 Ala Leu Phe Val              20 <210> 56 <211> 20 <212> PRT <213> Homo sapiens <400> 56 Leu Val Ala Pro Ser Cys Ala Tyr Gln Val Cys Gly Pro Pro Leu Tyr   1 5 10 15 Gln Leu Gly Ala              20 <210> 57 <211> 20 <212> PRT <213> Homo sapiens <400> 57 Ala Thr Gln Ala Arg Pro Pro His His Ala Ser Gly Pro Arg Arg Arg   1 5 10 15 Leu Gly Cys Glu              20 <210> 58 <211> 20 <212> PRT <213> Homo sapiens <400> 58 Arg Ala Trp Asn His Ser Val Arg Glu Ala Gly Val Pro Leu Gly Leu   1 5 10 15 Pro Ala Pro Gly              20 <210> 59 <211> 20 <212> PRT <213> Homo sapiens <400> 59 Ala Arg Arg Arg Gly Gly Ser Ala Ser Arg Ser Leu Pro Leu Pro Lys   1 5 10 15 Arg Pro Arg Arg              20 <210> 60 <211> 20 <212> PRT <213> Homo sapiens <400> 60 Gly Ala Ala Pro Glu Pro Glu Arg Thr Pro Val Gly Gln Gly Ser Trp   1 5 10 15 Ala His Pro Gly              20 <210> 61 <211> 20 <212> PRT <213> Homo sapiens <400> 61 Arg Thr Arg Gly Pro Ser Asp Arg Gly Phe Cys Val Val Ser Pro Ala   1 5 10 15 Arg Pro Ala Glu              20 <210> 62 <211> 20 <212> PRT <213> Homo sapiens <400> 62 Glu Ala Thr Ser Leu Glu Gly Ala Leu Ser Gly Thr Arg His Ser His   1 5 10 15 Pro Ser Val Gly              20 <210> 63 <211> 20 <212> PRT <213> Homo sapiens <400> 63 Arg Gln His His Ala Gly Pro Pro Ser Thr Ser Arg Pro Pro Arg Pro   1 5 10 15 Trp Asp Thr Pro              20 <210> 64 <211> 20 <212> PRT <213> Homo sapiens <400> 64 Cys Pro Pro Val Tyr Ala Glu Thr Lys His Phe Leu Tyr Ser Ser Gly   1 5 10 15 Asp Lys Glu Gln              20 <210> 65 <211> 20 <212> PRT <213> Homo sapiens <400> 65 Leu Arg Pro Ser Phe Leu Leu Ser Ser Leu Arg Pro Ser Leu Thr Gly   1 5 10 15 Ala Arg Arg Leu              20 <210> 66 <211> 20 <212> PRT <213> Homo sapiens <400> 66 Val Glu Thr Ile Phe Leu Gly Ser Arg Pro Trp Met Pro Gly Thr Pro   1 5 10 15 Arg Arg Leu Pro              20 <210> 67 <211> 20 <212> PRT <213> Homo sapiens <400> 67 Arg Leu Pro Gln Arg Tyr Trp Gln Met Arg Pro Leu Phe Leu Glu Leu   1 5 10 15 Leu Gly Asn His              20 <210> 68 <211> 20 <212> PRT <213> Homo sapiens <400> 68 Ala Gln Cys Pro Tyr Gly Val Leu Leu Lys Thr His Cys Pro Leu Arg   1 5 10 15 Ala Ala Val Thr              20 <210> 69 <211> 20 <212> PRT <213> Homo sapiens <400> 69 Pro Ala Ala Gly Val Cys Ala Arg Glu Lys Pro Gln Gly Ser Val Ala   1 5 10 15 Ala Pro Glu Glu              20 <210> 70 <211> 20 <212> PRT <213> Homo sapiens <400> 70 Glu Asp Thr Asp Pro Arg Arg Leu Val Gln Leu Leu Arg Gln His Ser   1 5 10 15 Ser Pro Trp Gln              20 <210> 71 <211> 20 <212> PRT <213> Homo sapiens <400> 71 Val Tyr Gly Phe Val Arg Ala Cys Leu Arg Arg Leu Val Pro Pro Gly   1 5 10 15 Leu Trp Gly Ser              20 <210> 72 <211> 20 <212> PRT <213> Homo sapiens <400> 72 Arg His Asn Glu Arg Arg Phe Leu Arg Asn Thr Lys Lys Phe Ile Ser   1 5 10 15 Leu Gly Lys His              20 <210> 73 <211> 20 <212> PRT <213> Homo sapiens <400> 73 Ala Lys Leu Ser Leu Gln Glu Leu Thr Trp Lys Met Ser Val Arg Asp   1 5 10 15 Cys Ala Trp Leu              20 <210> 74 <211> 20 <212> PRT <213> Homo sapiens <400> 74 Arg Arg Ser Pro Gly Val Gly Cys Val Pro Ala Ala Glu His Arg Leu   1 5 10 15 Arg Glu Glu Ile              20 <210> 75 <211> 20 <212> PRT <213> Homo sapiens <400> 75 Leu Ala Lys Phe Leu His Trp Leu Met Ser Val Tyr Val Val Glu Leu   1 5 10 15 Leu Arg Ser Phe              20 <210> 76 <211> 20 <212> PRT <213> Homo sapiens <400> 76 Phe Tyr Val Thr Glu Thr Thr Phe Gln Lys Asn Arg Leu Phe Phe Tyr   1 5 10 15 Arg Lys Ser Val              20 <210> 77 <211> 20 <212> PRT <213> Homo sapiens <400> 77 Trp Ser Lys Leu Gln Ser Ile Gly Ile Arg Gln His Leu Lys Arg Val   1 5 10 15 Gln Leu Arg Glu              20 <210> 78 <211> 20 <212> PRT <213> Homo sapiens <400> 78 Leu Ser Glu Ala Glu Val Arg Gln His Arg Glu Ala Arg Pro Ala Leu   1 5 10 15 Leu Thr Ser Arg              20 <210> 79 <211> 20 <212> PRT <213> Homo sapiens <400> 79 Leu Arg Phe Ile Pro Lys Pro Asp Gly Leu Arg Pro Ile Val Asn Met   1 5 10 15 Asp Tyr Val Val              20 <210> 80 <211> 20 <212> PRT <213> Homo sapiens <400> 80 Gly Ala Arg Thr Phe Arg Arg Glu Lys Arg Ala Glu Arg Leu Thr Ser   1 5 10 15 Arg Val Lys Ala              20 <210> 81 <211> 20 <212> PRT <213> Homo sapiens <400> 81 Leu Phe Ser Val Leu Asn Tyr Glu Arg Ala Arg Arg Pro Gly Leu Leu   1 5 10 15 Gly Ala Ser Val              20 <210> 82 <211> 20 <212> PRT <213> Homo sapiens <400> 82 Leu Gly Leu Asp Asp Ile His Arg Ala Trp Arg Thr Phe Val Leu Arg   1 5 10 15 Val Arg Ala Gln              20 <210> 83 <211> 20 <212> PRT <213> Homo sapiens <400> 83 Asp Pro Pro Glu Leu Tyr Phe Val Lys Val Asp Val Thr Gly Ala   1 5 10 15 Tyr Asp Thr Ile              20 <210> 84 <211> 20 <212> PRT <213> Homo sapiens <400> 84 Pro Gln Asp Arg Leu Thr Glu Val Ile Ala Ser Ile Ile Lys Pro Gln   1 5 10 15 Asn Thr Tyr Cys              20 <210> 85 <211> 20 <212> PRT <213> Homo sapiens <400> 85 Val Arg Arg Tyr Ala Val Val Gln Lys Ala Ala His Gly His Val Arg   1 5 10 15 Lys Ala Phe Lys              20 <210> 86 <211> 20 <212> PRT <213> Homo sapiens <400> 86 Ser His Val Ser Thr Leu Thr Asp Leu Gln Pro Tyr Met Arg Gln Phe   1 5 10 15 Val Ala His Leu              20 <210> 87 <211> 20 <212> PRT <213> Homo sapiens <400> 87 Gln Glu Thr Ser Pro Leu Arg Asp Ala Val Val Ile Glu Gln Ser Ser   1 5 10 15 Ser Leu Asn Glu              20 <210> 88 <211> 20 <212> PRT <213> Homo sapiens <400> 88 Ala Ser Ser Gly Leu Phe Asp Val Phe Leu Arg Phe Met Cys His His   1 5 10 15 Ala Val Arg Ile              20 <210> 89 <211> 20 <212> PRT <213> Homo sapiens <400> 89 Arg Gly Lys Ser Tyr Val Gln Cys Gln Gly Ile Pro Gln Gly Ser Ile   1 5 10 15 Leu Ser Thr Leu              20 <210> 90 <211> 20 <212> PRT <213> Homo sapiens <400> 90 Leu Cys Ser Leu Cys Tyr Gly Asp Met Glu Asn Lys Leu Phe Ala Gly   1 5 10 15 Ile Arg Arg Asp              20 <210> 91 <211> 20 <212> PRT <213> Homo sapiens <400> 91 Gly Leu Leu Leu Arg Leu Val Asp Asp Phe Leu Leu Val Thr Pro His   1 5 10 15 Leu Thr His Ala              20 <210> 92 <211> 20 <212> PRT <213> Homo sapiens <400> 92 Lys Thr Phe Leu Arg Thr Leu Val Arg Gly Val Pro Glu Tyr Gly Cys   1 5 10 15 Val Val Asn Leu              20 <210> 93 <211> 20 <212> PRT <213> Homo sapiens <400> 93 Arg Lys Thr Val Val Asn Phe Pro Val Glu Asp Glu Ala Leu Gly Gly   1 5 10 15 Thr Ala Phe Val              20 <210> 94 <211> 20 <212> PRT <213> Homo sapiens <400> 94 Gln Met Pro Ala His Gly Leu Phe Pro Trp Cys Gly Leu Leu Leu Asp   1 5 10 15 Thr Arg Thr Leu              20 <210> 95 <211> 20 <212> PRT <213> Homo sapiens <400> 95 Glu Val Gln Ser Asp Tyr Ser Ser Tyr Ala Arg Thr Ser Ile Arg Ala   1 5 10 15 Ser Leu Thr Phe              20 <210> 96 <211> 20 <212> PRT <213> Homo sapiens <400> 96 Asn Arg Gly Phe Lys Ala Gly Arg Asn Met Arg Arg Lys Leu Phe Gly   1 5 10 15 Val Leu Arg Leu              20 <210> 97 <211> 20 <212> PRT <213> Homo sapiens <400> 97 Lys Cys His Ser Leu Phe Leu Asp Leu Gln Val Asn Ser Leu Gln Thr   1 5 10 15 Val Cys Thr Asn              20 <210> 98 <211> 20 <212> PRT <213> Homo sapiens <400> 98 Ile Tyr Lys Ile Leu Leu Leu Gln Ala Tyr Arg Phe His Ala Cys Val   1 5 10 15 Leu Gln Leu Pro              20 <210> 99 <211> 20 <212> PRT <213> Homo sapiens <400> 99 Phe His Gln Gln Val Trp Lys Asn Pro Thr Phe Leu Arg Val Ile   1 5 10 15 Ser Asp Thr Ala              20 <210> 100 <211> 20 <212> PRT <213> Homo sapiens <400> 100 Ser Leu Cys Tyr Ser Ile Leu Lys Ala Lys Asn Ala Gly Met Ser Leu   1 5 10 15 Gly Ala Lys Gly              20 <210> 101 <211> 20 <212> PRT <213> Homo sapiens <400> 101 Ala Ala Gly Pro Leu Pro Ser Glu Ala Val Gln Trp Leu Cys His Gln   1 5 10 15 Ala Phe Leu Leu              20 <210> 102 <211> 20 <212> PRT <213> Homo sapiens <400> 102 Lys Leu Thr Arg His Arg Val Thr Tyr Val Leu Leu Gly Ser Leu   1 5 10 15 Arg Thr Ala Gln              20 <210> 103 <211> 20 <212> PRT <213> Homo sapiens <400> 103 Thr Gln Leu Ser Arg Lys Leu Pro Gly Thr Thr Leu Thr Ala Leu Glu   1 5 10 15 Ala Ala Ala Asn              20 <210> 104 <211> 12 <212> PRT <213> Homo sapiens <400> 104 Pro Ala Leu Pro Ser Asp Phe Lys Thr Ile Leu Asp   1 5 10 <210> 105 <211> 10 <212> PRT <213> Homo sapiens <400> 105 Met Pro Arg Ala Pro Arg Cys Arg Ala Val   1 5 10 <210> 106 <211> 20 <212> PRT <213> Homo sapiens <400> 106 Arg Ser Leu Leu Arg Ser His Tyr Arg Glu Val Leu Pro Leu Ala Thr   1 5 10 15 Phe Val Arg Arg              20 <210> 107 <211> 20 <212> PRT <213> Homo sapiens <400> 107 Leu Gly Pro Gln Gly Trp Arg Leu Val Gln Arg Gly Asp Pro Ala Ala   1 5 10 15 Phe Arg Ala Leu              20 <210> 108 <211> 20 <212> PRT <213> Homo sapiens <400> 108 Val Ala Gln Cys Leu Val Cys Val Pro Trp Asp Ala Arg Pro Pro Pro   1 5 10 15 Ala Ala Pro Ser              20 <210> 109 <211> 20 <212> PRT <213> Homo sapiens <400> 109 Phe Arg Gln Val Ser Cys Leu Lys Glu Leu Val Ala Arg Val Leu Gln   1 5 10 15 Arg Leu Cys Glu              20 <210> 110 <211> 20 <212> PRT <213> Homo sapiens <400> 110 Arg Gly Ala Lys Asn Val Leu Ala Phe Gly Phe Ala Leu Leu Asp Gly   1 5 10 15 Ala Arg Gly Gly              20 <210> 111 <211> 20 <212> PRT <213> Homo sapiens <400> 111 Pro Pro Glu Ala Phe Thr Thr Ser Val Arg Ser Tyr Leu Pro Asn Thr   1 5 10 15 Val Thr Asp Ala              20 <210> 112 <211> 20 <212> PRT <213> Homo sapiens <400> 112 Leu Arg Gly Ser Gly Ala Trp Gly Leu Leu Leu Arg Arg Val Gly Asp   1 5 10 15 Asp Val Leu Val              20 <210> 113 <211> 20 <212> PRT <213> Homo sapiens <400> 113 His Leu Leu Ala Arg Cys Ala Leu Phe Val Leu Val Ala Pro Ser Cys   1 5 10 15 Ala Tyr Gln Val              20 <210> 114 <211> 20 <212> PRT <213> Homo sapiens <400> 114 Cys Gly Pro Pro Leu Tyr Gln Leu Gly Ala Ala Thr Gln Ala Arg Pro   1 5 10 15 Pro Pro His Ala              20 <210> 115 <211> 20 <212> PRT <213> Homo sapiens <400> 115 Ser Gly Pro Arg Arg Leu Gly Cys Glu Arg Ala Trp Asn His Ser   1 5 10 15 Val Arg Glu Ala              20 <210> 116 <211> 20 <212> PRT <213> Homo sapiens <400> 116 Gly Val Pro Leu Gly Leu Pro Ala Pro Gly Ala Arg Arg Arg Gly Gly   1 5 10 15 Ser Ala Ser Arg              20 <210> 117 <211> 20 <212> PRT <213> Homo sapiens <400> 117 Ser Leu Pro Leu Pro Lys Arg Pro Arg Arg Gly Ala Ala Pro Glu Pro   1 5 10 15 Glu Arg Thr Pro              20 <210> 118 <211> 20 <212> PRT <213> Homo sapiens <400> 118 Val Gly Gln Gly Ser Trp Ala His Pro Gly Arg Thr Arg Gly Pro Ser   1 5 10 15 Asp Arg Gly Phe              20 <210> 119 <211> 20 <212> PRT <213> Homo sapiens <400> 119 Cys Val Val Ser Pro Ala Arg Pro Ala Glu Glu Ala Thr Ser Leu Glu   1 5 10 15 Gly Ala Leu Ser              20 <210> 120 <211> 20 <212> PRT <213> Homo sapiens <400> 120 Gly Thr Arg His Ser Pro Ser Val Gly Arg Gln His His Ala Gly   1 5 10 15 Pro Pro Ser Thr              20 <210> 121 <211> 20 <212> PRT <213> Homo sapiens <400> 121 Ser Arg Pro Pro Arg Pro Trp Asp Thr Pro Cys Pro Pro Val Tyr Ala   1 5 10 15 Glu Thr Lys His              20 <210> 122 <211> 20 <212> PRT <213> Homo sapiens <400> 122 Phe Leu Tyr Ser Ser Gly Asp Lys Glu Gln Leu Arg Pro Ser Phe Leu   1 5 10 15 Leu Ser Ser Leu              20 <210> 123 <211> 20 <212> PRT <213> Homo sapiens <400> 123 Arg Pro Ser Leu Thr Gly Ala Arg Arg Leu Val Glu Thr Ile Phe Leu   1 5 10 15 Gly Ser Arg Pro              20 <210> 124 <211> 20 <212> PRT <213> Homo sapiens <400> 124 Trp Met Pro Gly Thr Pro Arg Arg Leu Pro Arg Leu Pro Gln Arg Tyr   1 5 10 15 Trp Gln Met Arg              20 <210> 125 <211> 20 <212> PRT <213> Homo sapiens <400> 125 Pro Leu Phe Leu Glu Leu Leu Gly Asn His Ala Gln Cys Pro Tyr Gly   1 5 10 15 Val Leu Leu Lys              20 <210> 126 <211> 20 <212> PRT <213> Homo sapiens <400> 126 Thr His Cys Pro Leu Arg Ala Ala Val Thr Pro Ala Ala Gly Val Cys   1 5 10 15 Ala Arg Glu Lys              20 <210> 127 <211> 20 <212> PRT <213> Homo sapiens <400> 127 Pro Gln Gly Ser Val Ala Pro Glu Glu Glu Asp Thr Asp Pro Arg   1 5 10 15 Arg Leu Val Gln              20 <210> 128 <211> 20 <212> PRT <213> Homo sapiens <400> 128 Leu Leu Arg Gln His Ser Ser Pro Trp Gln Val Tyr Gly Phe Val Arg   1 5 10 15 Ala Cys Leu Arg              20 <210> 129 <211> 20 <212> PRT <213> Homo sapiens <400> 129 Arg Leu Val Pro Pro Gly Leu Trp Gly Ser Arg His His Gn Arg Arg   1 5 10 15 Phe Leu Arg Asn              20 <210> 130 <211> 20 <212> PRT <213> Homo sapiens <400> 130 Thr Lys Lys Phe Ile Ser Leu Gly Lys His Ala Lys Leu Ser Leu Gln   1 5 10 15 Glu Leu Thr Trp              20 <210> 131 <211> 20 <212> PRT <213> Homo sapiens <400> 131 Lys Met Ser Val Arg Asp Cys Ala Trp Leu Arg Arg Ser Ser Gly Val   1 5 10 15 Gly Cys Val Pro              20 <210> 132 <211> 20 <212> PRT <213> Homo sapiens <400> 132 Ala Ala Glu His Arg Leu Arg Glu Glu Ile Leu Ala Lys Phe Leu His   1 5 10 15 Trp Leu Met Ser              20 <210> 133 <211> 20 <212> PRT <213> Homo sapiens <400> 133 Val Tyr Val Val Glu Leu Leu Arg Ser Phe Phe Tyr Val Thr Glu Thr   1 5 10 15 Thr Phe Gln Lys              20 <210> 134 <211> 20 <212> PRT <213> Homo sapiens <400> 134 Asn Arg Leu Phe Phe Tyr Arg Lys Ser Val Trp Ser Lys Leu Gln Ser   1 5 10 15 Ile Gly Ile Arg              20 <210> 135 <211> 20 <212> PRT <213> Homo sapiens <400> 135 Gln His Leu Lys Arg Val Gln Leu Arg Glu Leu Ser Glu Ala Glu Val   1 5 10 15 Arg Gln His Arg              20 <210> 136 <211> 20 <212> PRT <213> Homo sapiens <400> 136 Glu Ala Arg Pro Ala Leu Leu Thr Ser Arg Leu Arg Phe Ile Pro Lys   1 5 10 15 Pro Asp Gly Leu              20 <210> 137 <211> 20 <212> PRT <213> Homo sapiens <400> 137 Arg Pro Ile Val Asn Met Asp Tyr Val Val Gly Ala Arg Thr Phe Arg   1 5 10 15 Arg Glu Lys Arg              20 <210> 138 <211> 20 <212> PRT <213> Homo sapiens <400> 138 Ala Glu Arg Leu Thr Ser Arg Val Lys Ala Leu Phe Ser Val Leu Asn   1 5 10 15 Tyr Glu Arg Ala              20 <210> 139 <211> 20 <212> PRT <213> Homo sapiens <400> 139 Arg Arg Pro Gly Leu Leu Gly Ala Ser Val Leu Gly Leu Asp Asp Ile   1 5 10 15 His Arg Ala Trp              20 <210> 140 <211> 20 <212> PRT <213> Homo sapiens <400> 140 Arg Thr Phe Val Leu Arg Val Arg Ala Gln Asp Pro Pro Pro Glu Leu   1 5 10 15 Tyr Phe Val Lys              20 <210> 141 <211> 20 <212> PRT <213> Homo sapiens <400> 141 Val Asp Val Thr Gly Ala Tyr Asp Thr Ile Pro Gln Asp Arg Leu Thr   1 5 10 15 Glu Val Ile Ala              20 <210> 142 <211> 20 <212> PRT <213> Homo sapiens <400> 142 Ser Ile Ile Lys Pro Gln Asn Thr Tyr Cys Val Arg Arg Tyr Ala Val   1 5 10 15 Val Gln Lys Ala              20 <210> 143 <211> 20 <212> PRT <213> Homo sapiens <400> 143 Ala His Gly His Val Arg Lys Ala Phe Lys Ser His Val Ser Thr Leu   1 5 10 15 Thr Asp Leu Gln              20 <210> 144 <211> 20 <212> PRT <213> Homo sapiens <400> 144 Pro Tyr Met Arg Gln Phe Val Ala His Leu Gln Glu Thr Ser Pro Leu   1 5 10 15 Arg Asp Ala Val              20 <210> 145 <211> 20 <212> PRT <213> Homo sapiens <400> 145 Val Ile Glu Gln Ser Ser Ser Leu Asn Glu Ala Ser Ser Gly Leu Phe   1 5 10 15 Asp Val Phe Leu              20 <210> 146 <211> 20 <212> PRT <213> Homo sapiens <400> 146 Arg Phe Met Cys His His Ala Val Arg Ile Arg Gly Lys Ser Tyr Val   1 5 10 15 Gln Cys Gln Gly              20 <210> 147 <211> 20 <212> PRT <213> Homo sapiens <400> 147 Ile Pro Gln Gly Ser Ile Leu Ser Thr Leu Leu Cys Ser Leu Cys Tyr   1 5 10 15 Gly Asp Met Glu              20 <210> 148 <211> 20 <212> PRT <213> Homo sapiens <400> 148 Asn Lys Leu Phe Ala Gly Ile Arg Arg Asp Gly Leu Leu Leu Arg Leu   1 5 10 15 Val Asp Asp Phe              20 <210> 149 <211> 20 <212> PRT <213> Homo sapiens <400> 149 Leu Leu Val Thr Pro His Leu Thr His Ala Lys Thr Phe Leu Arg Thr   1 5 10 15 Leu Val Arg Gly              20 <210> 150 <211> 20 <212> PRT <213> Homo sapiens <400> 150 Val Pro Glu Tyr Gly Cys Val Val Asn Leu Arg Lys Thr Val Val Asn   1 5 10 15 Phe Pro Val Glu              20 <210> 151 <211> 20 <212> PRT <213> Homo sapiens <400> 151 Asp Glu Ala Leu Gly Gly Thr Ala Phe Val Gln Met Pro Ala His Gly   1 5 10 15 Leu Phe Pro Trp              20 <210> 152 <211> 20 <212> PRT <213> Homo sapiens <400> 152 Cys Gly Leu Leu Leu Asp Thr Arg Thr Leu Glu Val Gln Ser Asp Tyr   1 5 10 15 Ser Ser Tyr Ala              20 <210> 153 <211> 20 <212> PRT <213> Homo sapiens <400> 153 Arg Thr Ser Ile Arg Ala Ser Leu Thr Phe Asn Arg Gly Phe Lys Ala   1 5 10 15 Gly Arg Asn Met              20 <210> 154 <211> 20 <212> PRT <213> Homo sapiens <400> 154 Arg Arg Lys Leu Phe Gly Val Leu Arg Leu Lys Cys His Ser Leu Phe   1 5 10 15 Leu Asp Leu Gln              20 <210> 155 <211> 20 <212> PRT <213> Homo sapiens <400> 155 Val Asn Ser Leu Gln Thr Val Cys Thr Asn Ile Tyr Lys Ile Leu Leu   1 5 10 15 Leu Gln Ala Tyr              20 <210> 156 <211> 20 <212> PRT <213> Homo sapiens <400> 156 Arg Phe His Ala Cys Val Leu Gln Leu Pro Phe His Gln Gln Val Trp   1 5 10 15 Lys Asn Pro Thr              20 <210> 157 <211> 20 <212> PRT <213> Homo sapiens <400> 157 Phe Phe Leu Arg Val Ile Ser Asp Thr Ala Ser Leu Cys Tyr Ser Ile   1 5 10 15 Leu Lys Ala Lys              20 <210> 158 <211> 20 <212> PRT <213> Homo sapiens <400> 158 Asn Gly Aly Gly Aly Gly Aly Gly Aly Gly Aly Gly Aly Gly Aly Gly   1 5 10 15 Ser Glu Ala Val              20 <210> 159 <211> 20 <212> PRT <213> Homo sapiens <400> 159 Gln Trp Leu Cys His Gln Ala Phe Leu Leu Lys Leu Thr Arg His Arg   1 5 10 15 Val Thr Tyr Val              20 <210> 160 <211> 20 <212> PRT <213> Homo sapiens <400> 160 Pro Leu Leu Gly Ser Leu Arg Thr Ala Gln Thr Gln Leu Ser Arg Lys   1 5 10 15 Leu Pro Gly Thr              20 <210> 161 <211> 22 <212> PRT <213> Homo sapiens <400> 161 Thr Leu Thr Ala Leu Glu Ala Ala Ala Asn Pro Ala Leu Pro Ser Asp   1 5 10 15 Phe Lys Thr Ile Leu Asp              20 <210> 162 <211> 1132 <212> PRT <213> Homo sapiens <400> 162 Met Pro Arg Ala Pro Arg Cys Arg Ala Val Arg Ser Leu Leu Arg Ser   1 5 10 15 His Tyr Arg Glu Val Leu Pro Leu Ala Thr Phe Val Arg Arg Leu Gly              20 25 30 Pro Gln Gly Trp Arg Leu Val Gln Arg Gly Asp Pro Ala Ala Phe Arg          35 40 45 Ala Leu Val Ala Gln Cys Leu Val Cys Val Pro Trp Asp Ala Arg Pro      50 55 60 Pro Pro Ala Ala Pro Ser Phe Arg Gln Val Ser Cys Leu Lys Glu Leu  65 70 75 80 Val Ala Arg Val Leu Gln Arg Leu Cys Glu Arg Gly Ala Lys Asn Val                  85 90 95 Leu Ala Phe Gly Phe Ala Leu Leu Asp Gly Ala Arg Gly Gly Pro Pro             100 105 110 Glu Ala Phe Thr Thr Ser Val Arg Ser Tyr Leu Pro Asn Thr Val Thr         115 120 125 Asp Ala Leu Arg Gly Ser Gly Ala Trp Gly Leu Leu Leu Arg Arg Val     130 135 140 Gly Asp Asp Val Leu Val His Leu Leu Ala Arg Cys Ala Leu Phe Val 145 150 155 160 Leu Val Ala Pro Ser Cys Ala Tyr Gln Val Cys Gly Pro Pro Leu Tyr                 165 170 175 Gln Leu Gly Ala Ala Thr Gln Ala Arg Pro Pro His Ala Ser Gly             180 185 190 Pro Arg Arg Arg Leu Gly Cys Glu Arg Ala Trp Asn His Ser Val Arg         195 200 205 Glu Ala Gly Val Pro Leu Gly Leu Pro Ala Pro Gly Ala Arg Arg Arg     210 215 220 Gly Gly Ser Ala Ser Arg Ser Leu Pro Leu Pro Lys Arg Pro Arg Arg 225 230 235 240 Gly Ala Ala Pro Glu Pro Glu Arg Thr Pro Val Gly Gln Gly Ser Trp                 245 250 255 Ala His Pro Gly Arg Thr Arg Gly Pro Ser Asp Arg Gly Phe Cys Val             260 265 270 Val Ser Pro Ala Arg Pro Ala Glu Glu Ala Thr Ser Leu Glu Gly Ala         275 280 285 Leu Ser Gly Thr Arg His Ser Ser Ser Val Gly Arg Gln His His     290 295 300 Ala Gly Pro Pro Ser Thr Ser Arg Pro Pro Arg Pro Trp Asp Thr Pro 305 310 315 320 Cys Pro Pro Val Tyr Ala Glu Thr Lys His Phe Leu Tyr Ser Ser Gly                 325 330 335 Asp Lys Glu Gln Leu Arg Pro Ser Phe Leu Leu Ser Ser Leu Arg Pro             340 345 350 Ser Leu Thr Gly Ala Arg Arg Leu Val Glu Thr Ile Phe Leu Gly Ser         355 360 365 Arg Pro Trp Met Pro Gly Thr Pro Arg Arg Leu Pro Arg Leu Pro Gln     370 375 380 Arg Tyr Trp Gln Met Arg Pro Leu Phe Leu Glu Leu Leu Gly Asn His 385 390 395 400 Ala Gln Cys Pro Tyr Gly Val Leu Leu Lys Thr His Cys Pro Leu Arg                 405 410 415 Ala Ala Val Thr Pro Ala Ala Gly Val Cys Ala Arg Glu Lys Pro Gln             420 425 430 Gly Ser Val Ala Ala Pro Glu Glu Glu Asp Thr Asp Pro Arg Arg Leu         435 440 445 Val Gln Leu Leu Arg Gln His Ser Ser Pro Trp Gln Val Tyr Gly Phe     450 455 460 Val Arg Ala Cys Leu Arg Arg Leu Val Pro Pro Gly Leu Trp Gly Ser 465 470 475 480 Arg His Asn Glu Arg Arg Phe Leu Arg Asn Thr Lys Lys Phe Ile Ser                 485 490 495 Leu Gly Lys His Ala Lys Leu Ser Leu Gln Glu Leu Thr Trp Lys Met             500 505 510 Ser Val Arg Asp Cys Ala Trp Leu Arg Arg Ser Pro Gly Val Gly Cys         515 520 525 Val Pro Ala Ala Glu His Arg Leu Arg Glu Glu Ile Leu Ala Lys Phe     530 535 540 Leu His Trp Leu Met Ser Val Tyr Val Val Glu Leu Leu Arg Ser Phe 545 550 555 560 Phe Tyr Val Thr Glu Thr Thr Phe Gln Lys Asn Arg Leu Phe Phe Tyr                 565 570 575 Arg Lys Ser Val Trp Ser Lys Leu Gln Ser Ile Gly Ile Arg Gln His             580 585 590 Leu Lys Arg Val Gln Leu Arg Glu Leu Ser Glu Ala Glu Val Arg Gln         595 600 605 His Arg Glu Ala Arg Pro Ala Leu Leu Thr Ser Arg Leu Arg Phe Ile     610 615 620 Pro Lys Pro Asp Gly Leu Arg Pro Ile Val Asn Met Asp Tyr Val Val 625 630 635 640 Gly Ala Arg Thr Phe Arg Arg Glu Lys Arg Ala Glu Arg Leu Thr Ser                 645 650 655 Arg Val Lys Ala Leu Phe Ser Val Leu Asn Tyr Glu Arg Ala Arg Arg             660 665 670 Pro Gly Leu Leu Gly Ala Ser Val Leu Gly Leu Asp Asp Ile His Arg         675 680 685 Ala Trp Arg Thr Phe Val Leu Arg Val Arg Ala Gln Asp Pro Pro Pro     690 695 700 Glu Leu Tyr Phe Val Lys Val Asp Val Thr Gly Ala Tyr Asp Thr Ile 705 710 715 720 Pro Gln Asp Arg Leu Thr Glu Val Ile Ala Ser Ile Ile Lys Pro Gln                 725 730 735 Asn Thr Tyr Cys Val Arg Arg Tyr Ala Val Val Gln Lys Ala Ala His             740 745 750 Gly His Val Arg Lys Ala Phe Lys Ser His Val Ser Thr Leu Thr Asp         755 760 765 Leu Gln Pro Tyr Met Arg Gln Phe Val Ala His Leu Gln Glu Thr Ser     770 775 780 Pro Leu Arg Asp Ala Val Valle Glu Gln Ser Ser Ser Leu Asn Glu 785 790 795 800 Ala Ser Ser Gly Leu Phe Asp Val Phe Leu Arg Phe Met Cys His His                 805 810 815 Ala Val Arg Ile Arg Gly Lys Ser Tyr Val Gln Cys Gln Gly Ile Pro             820 825 830 Gln Gly Ser Ile Leu Ser Thr Leu Leu Cys Ser Leu Cys Tyr Gly Asp         835 840 845 Met Glu Asn Lys Leu Phe Ala Gly Ile Arg Arg Asp Gly Leu Leu Leu     850 855 860 Arg Leu Val Asp Asp Phe Leu Leu Val Thr Pro His Leu Thr His Ala 865 870 875 880 Lys Thr Phe Leu Arg Thr Leu Val Arg Gly Val Pro Glu Tyr Gly Cys                 885 890 895 Val Val Asn Leu Arg Lys Thr Val Val Asn Phe Pro Val Glu Asp Glu             900 905 910 Ala Leu Gly Gly Thr Ala Phe Val Gln Met Pro Ala His Gly Leu Phe         915 920 925 Pro Trp Cys Gly Leu Leu Leu Asp Thr Arg Thr Leu Glu Val Gln Ser     930 935 940 Asp Tyr Ser Ser Tyr Ala Arg Thr Ser Ile Arg Ala Ser Leu Thr Phe 945 950 955 960 Asn Arg Gly Phe Lys Ala Gly Arg Asn Met Arg Arg Lys Leu Phe Gly                 965 970 975 Val Leu Arg Leu Lys Cys His Ser Leu Phe Leu Asp Leu Gln Val Asn             980 985 990 Ser Leu Gln Thr Val Cys Thr Asn Ile Tyr Lys Ile Leu Leu Leu Gln         995 1000 1005 Ala Tyr Arg Phe His Ala Cys Val Leu Gln Leu Pro Phe His Gln Gln    1010 1015 1020 Val Trp Lys Asn Pro Thr Phe Phe Leu Arg Val Ile Ser Asp Thr Ala 1025 1030 1035 1040 Ser Leu Cys Tyr Ser Ile Leu Lys Ala Lys Asn Ala Gly Met Ser Leu                1045 1050 1055 Gly Ala Lys Gly Ala Gly Pro Leu Pro Ser Glu Ala Val Gln Trp            1060 1065 1070 Leu Cys His Gln Ala Phe Leu Leu Lys Leu Thr Arg His Arg Val Thr        1075 1080 1085 Tyr Val Pro Leu Leu Gly Ser Leu Arg Thr Ala Gln Thr Gln Leu Ser    1090 1095 1100 Arg Lys Leu Pro Gly Thr Thr Leu Thr Ala Leu Glu Ala Ala Ala Asn 1105 1110 1115 1120 Pro Ala Leu Pro Ser Asp Phe Lys Thr Ile Leu Asp                1125 1130 <210> 163 <211> 16 <212> PRT <213> Homo sapiens <400> 163 Glu Ala Arg Pro Ala Leu Leu Thr Ser Arg Leu Arg Phe Ile Pro Lys   1 5 10 15

Claims (24)

As a peptide having TNF-a inhibitory activity,
A peptide comprising any one of the amino acid sequences of SEQ ID NOS: 1 to 161, a peptide having a sequence homology of 80% or more with the amino acid sequence, or a fragment thereof. 2. The peptide of claim 1, wherein the fragment is a fragment consisting of three or more amino acids. 2. The peptide of claim 1, wherein the peptide is composed of up to 30 amino acids. The method of claim 1, Wherein the peptide comprises an amino acid sequence of any one of SEQ ID NOS: 1-161. The method of claim 1, Wherein said peptide is an amino acid sequence comprising SEQ ID NO: 1. The method of claim 1, The peptide may be any one of SEQ ID NO: 1 to SEQ ID NO: 6, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 14 to 21, SEQ ID NO: 23 to SEQ ID NO: 37, SEQ ID NO: 39 to SEQ ID NO: 44, SEQ ID NO: 47 to SEQ ID NO: SEQ ID NO: 55, SEQ ID NO: 61, SEQ ID NO: 63 to SEQ ID NO: 82, SEQ ID NO: 84 to SEQ ID NO: 94, SEQ ID NO: 96, SEQ ID NO: 99 to SEQ ID NO: 104, SEQ ID NO: 107 to SEQ ID NO: 109, SEQ ID NO: , SEQ ID NO: 120 to SEQ ID NO: 122, SEQ ID NO: 124, SEQ ID NO: 129 to SEQ ID NO: 133, SEQ ID NO: 142 to SEQ ID NO: 144, SEQ ID NO: 146, SEQ ID NO: 148, SEQ ID NO: 149 and SEQ ID NO: 155 to SEQ ID NO: Lt; RTI ID = 0.0 &gt; 1, &lt; / RTI &gt; The method of claim 6, SEQ ID NO: 18, SEQ ID NO: 29, SEQ ID NO: 29, SEQ ID NO: 31 to SEQ ID NO: 34, SEQ ID NO: 39 to SEQ ID NO: 41, SEQ ID NO: 47, SEQ ID NO: SEQ ID NO: 53, SEQ ID NO: 55 to SEQ ID NO: 58, SEQ ID NO: 61, SEQ ID NO: 65 to SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 73 to SEQ ID NO: 79, SEQ ID NO: 81, SEQ ID NO: SEQ ID NO: 90, SEQ ID NO: 94, SEQ ID NO: 94, SEQ ID NO: 99, SEQ ID NO: 101 to SEQ ID NO: 104, SEQ ID NO: 107 to SEQ ID NO: 109, SEQ ID NO: 120, SEQ ID NO: 121, SEQ ID NO: A peptide comprising any one of the amino acid sequences selected from the group consisting of SEQ ID NO: 132, SEQ ID NO: 142 to SEQ ID NO: 144, SEQ ID NO: 146, SEQ ID NO: 148, SEQ ID NO: 149 and SEQ ID NO: 157 to SEQ ID NO: The method of claim 1, SEQ ID NO: 1, SEQ ID NO: 5, SEQ ID NO: 6, , SEQ ID NO: 32 to SEQ ID NO: 53, SEQ ID NO: 55 to SEQ ID NO: 60, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72 to SEQ ID NO: 82, SEQ ID NO: 84 to SEQ ID NO: 92, SEQ ID NO: Any one selected from the group consisting of SEQ ID NO: 99 to SEQ ID NO: 112, SEQ ID NO: 114, SEQ ID NO: 127 to SEQ ID NO: 144, SEQ ID NO: 146, SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 151 and SEQ ID NO: 153 to SEQ ID NO: &Lt; / RTI &gt; 10. The method of claim 8, The peptide may be selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17 to SEQ ID NO: 23, SEQ ID NO: , SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 33 to SEQ ID NO: 43, SEQ ID NO: 156, SEQ ID NO: 157 and SEQ ID NO: 159. The method of claim 1, Wherein the peptide is derived from human telomerase. As polynucleotides encoding a peptide having TNF-a inhibitory activity,
A polynucleotide encoding a peptide comprising an amino acid sequence of any one of SEQ ID NOS: 1 to 161 or a peptide having a sequence homology of 80% or more with the amino acid sequence, or a peptide thereof. 12. The polynucleotide of claim 11, wherein the peptide encodes 30 or fewer amino acids. 12. The polynucleotide of claim 11, wherein the peptide comprises the amino acid sequence of any one of SEQ ID NOS: 1-161. 12. The peptide of claim 11, wherein the peptide is derived from human telomerase. A peptide comprising an amino acid sequence of any one of SEQ ID NOS: 1 to 161,
A peptide having a sequence homology of 80% or more with the amino acid sequence or a peptide thereof as an active ingredient. 16. The composition of claim 15, wherein the peptide is composed of up to 30 amino acids. 16. The composition according to claim 15, wherein the peptide comprises an amino acid sequence of any one of SEQ ID NOS: 1-116. 16. The composition of claim 15, wherein said peptide is derived from human telomerase. 16. The composition of claim 15, wherein said composition is for the treatment or prevention of a TNF-a mediated disorder. 16. The composition of claim 15, wherein the composition is a pharmaceutical composition for the treatment or prevention of TNF-a mediated diseases. 16. The composition of claim 15, wherein the composition is a food composition for the improvement or prevention of TNF-a mediated disease. 21. The method of claim 20, wherein the TNF-a mediated disease is selected from the group consisting of inflammatory bowel disease such as rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis, ulcerative colitis and Crohn's disease, ankylosing spondylitis, multiple sclerosis, systemic lupus erythematosus Chronic obstructive pulmonary disease (COPD), sepsis, endotoxic shock, hepatitis, and type 1 diabetes mellitus. 22. A method of preventing or treating a TNF-α mediated disease, which comprises administering a TNF-α inhibitory composition according to any one of claims 15 to 22. A peptide comprising an amino acid sequence of any one of SEQ ID NOS: 1 to 161, a peptide having a sequence homology of 80% or more with the amino acid sequence, or a peptide or fragment thereof, or a composition comprising the peptide; And a kit for the prevention or treatment of a TNF-a mediated disease, comprising an instruction that discloses one or more of the dose, administration route, number of doses and indications of the peptide or composition comprising the same.

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