JPH0625288A - Peptide or its salt - Google Patents

Abstract

PURPOSE:To obtain a peptide, useful for treating fracture, wound, multiple sclerosis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontosis, etc., and capable of effectively suppressing the rejection after organ transplantation. CONSTITUTION:This peptide or its salt has the following general formula: H- X 1-Ala-X 2-Pro-Cys-Cys-Val-X 3-Gln-X 4-Leu-Glu-X 5-Y (X 2 denotes an amino acid residue selected from the group consisting of Ser and Ala; X 3 denotes an amino acid residue selected from the group consisting of Ser and Pro; X 4 denotes an amino acid residue selected from the group consisting of Ala and Asp; X 1 and X 5 respectively denote single bonds or peptide fragments composed of 1-5 amino acid residues selected from the group consisting of Gly, Ala, Val, Arg, Asn, Ser, Phe, Pro, Leu, Glu, Asp, Lys, Thr, His, Tyr, Nle and Ile; Y denotes hydroxyl group or amino group) and transforming growth factor (TGF)-beta-like activity.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a peptide having TGF-β-like activity or a salt thereof. The peptide or its salt provided by the present invention has TGF-β-like activity, and thus is useful for the treatment of bone fracture, wound, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal disease, multiple sclerosis and the like. In addition, rejection after organ transplantation can be effectively suppressed.

[0002]

2. Description of the Related Art TGF (transforming growth factor) -β
Was discovered as a tumor-derived factor that expresses tumor-like properties in non-tumor cells, and was subsequently discovered in normal tissues such as platelets, macrophages, bones and kidneys (Clinical Immunity, Vol. 24, p. 146 ( 1992))). Active TG
F-β exists as a homodimer having a molecular weight of approximately 25 kD (Proceeds of the National Academy of Sciences of the United States of America (Proc. Natl. Acad. Sci.
USA.), Vol. 85, p. 4715 (1988)), which causes reversible transformation of NRK-49F strain, a rat normal fibroblast, and promotes growth on soft agar medium. Although it has an action, it has been clarified that it acts as a growth inhibitor on many other cells (Current Topics in Developmental Biology),
Vol. 24, page 95 (1990)).

Since TGF-β promotes vascularization and extracellular matrix protein synthesis, it is considered to have a fracture-bonding action or a wound-healing effect (Science, Vol. 237, See page 1333 (1987)).
Since TGF-β has a strong immunosuppressive action, it has been reported to suppress rejection after organ transplantation (Proceedings of the National Academy of Sciences of the United States of America (Proc. Natl. Acad.
Sci. USA.), Vol. 87, p. 1591 (1990)). Furthermore, TGF-β has been reported to be present in the synovial fluid of patients with rheumatoid arthritis and to neutralize the action of IL-1, a potent inflammatory mediator (The Journal).
Of Immunology (J. Immunol.), Volume 145, Volume 2514
Page (1990)). In addition, TGF-β promotes bone formation in vivo, and is therefore considered to be useful in the treatment of osteoporosis or periodontitis (Experimental Medicine, Vol. 8, 345).
(See page (1990)), it was also reported to suppress the development of experimental multiple sclerosis model animals (Proceedings of the National Academy of Sciences of the United States of
USA (Proc. Natl. Acad. Sci. USA.), Volume 88, Vol.
See page 2918 (1991)).

[0004]

The above-mentioned TGF-β is
Due to its large molecular weight, it is highly immunogenic, and repeated administration may cause anaphylactic shock.
Even when administered in vivo, it disappears from the blood within a few minutes and loses its effectiveness. In addition, administration of a large amount may cause various side effects such as toxicity to the liver and kidneys and nonspecific immunosuppression. However, the object of the present invention is to produce T with less side effects and stronger TGF-β.
It is to provide a peptide having GF-β-like activity.

[0005]

According to the present invention, the above object is achieved by the following general formula (I) H-X ↑ 1-Ala-X ↑ 2-Pro-Cys-Cys-Val-X ↑ 3. -Gln-X ↑ 4-Leu-Glu-X ↑ 5-Y (I) (In the formula, X ↑ 2 represents an amino acid residue selected from the group consisting of Ser and Ala, and X ↑ 3 represents Ser and Pro. Represents an amino acid residue selected from the group, X ↑ 4 represents an amino acid residue selected from the group consisting of Ala and Asp,
X ↑ 1 and X ↑ 5 are single bonds or Gly and Al, respectively.
a, Val, Arg, Asn, Ser, Phe, Pro, Leu, Gl
a peptide fragment consisting of 1 to 5 amino acid residues selected from the group consisting of u, Asp, Lys, Thr, His, Tyr, Nle and Ile, and Y represents a hydroxyl group or an amino group) or This is accomplished by providing the salt.

In the present specification, various amino acid residues are described by the following abbreviations. Ala: L-alanine residue Arg: L-arginine residue Asn: L-asparagine residue Asp: L-aspartic acid residue Cys: L-cysteine residue Gln: L-glutamine residue Glu: L-glutamic acid residue Gly: Glycine residue His: L-histidine residue Ile: L-isoleucine residue Leu: L-leucine residue Lys: L-lysine residue Phe: L-phenylalanine residue Pro: L-proline residue Ser: L -Serine residue Thr: L-threonine residue Trp: L-tryptophan residue Tyr: L-tyrosine residue Val: L-valine residue Nle: L-norleucine residue In this specification, according to a conventional method. The amino acid sequence of a peptide is described so that the N-terminal amino acid residue is located on the left and the C-terminal amino acid residue is located on the right.

Among the peptides represented by the above general formula (I), the following general formula (II) H-X ↑ 6-A-X ↑ 7-Y (II) (wherein A is the formula (1): Ala Ala Pro Cys Cys Val Pro
Peptide fragment represented by Gln Ala Leu Glu (SEQ ID NO: 1), Formula (2): Ala Ser Pro Cys Cys Val Pro Gln As
The peptide fragment represented by p Leu Glu (SEQ ID NO: 2) or the formula (3): Ala Ser Pro Cys Cys Val Ser Gln Asp
The peptide fragment represented by Leu Glu (SEQ ID NO: 3) is represented by X ↑ 6 and X ↑ 7 each being a single bond or Gly,
Ala, Val, Arg, Asn, Ser, Phe, Pro, Leu, G
a peptide fragment consisting of 1 to 5 amino acid residues selected from the group consisting of lu, Asp, Lys, Thr, His, Tyr, Nle and Ile, and Y represents a hydroxyl group or an amino group). preferable.

Representative examples of the peptides provided by the present invention are shown below. Formula (4): Asn Pro Gly Ala Ser Ala Ala Pro Cys Cys
Val Pro Gln Ala Leu Glu (SEQ ID NO: 4), Formula (5): Ala Ala Pro Cys Cys Val Pro Gln Ala Leu
Glu Pro Leu Pro Ile Val (SEQ ID NO: 5), Formula (6): Ala Pro Glu Ala Ser Ala Ser Pro Cys Cys
Val Pro Gln Asp Leu Glu (SEQ ID NO: 6), Formula (7): Ala Ser Pro Cys Cys Val Pro Gln Asp Leu
Glu Pro Leu Pro Ile Val (SEQ ID NO: 7), Formula (8): Asn Pro Gly Ala Ser Ala Ser Pro Cys Cys
Val Ser Gln Asp Leu Glu Pro Leu Thr Ile Leu (SEQ ID NO: 8) and Formula (9): Asn Pro Gly Ala Ser Ala Ser Pro Cys Cys
Val Ser Gln Asp Leu Glu Pro Leu Pro Ile Leu (SEQ ID NO: 9).

The salt of the peptide of the present invention is a physiologically acceptable salt. Examples of the salt include hydrochloric acid, sulfuric acid,
Salts with acids such as phosphoric acid, lactic acid, tartaric acid, maleic acid, fumaric acid, oxalic acid, malic acid, citric acid, oleic acid, palmitic acid; alkali metals or alkaline earth metals such as sodium, potassium, calcium and aluminum Salts with hydroxides or carbonates; salts with triethylamine, benzylamine, diethanolamine, t-butylamine, dicyclohexylamine, arginine and the like can be mentioned.

The peptide of the present invention is prepared by a method usually used in peptide synthesis, for example, a solid phase synthesis method or a liquid phase synthesis method, and the solid phase synthesis method is simple in operation (for example, the Japanese Biochemical Society). Volume "Sequel to Biochemistry Laboratory 2
Protein Chemistry (below), pp. 641-694 (Published by Tokyo Kagaku Dojin on May 20, 1987).

The preparation of the peptide of the present invention by the solid phase synthesis method can be carried out, for example, by using a polymer which is insoluble in a reaction solvent such as a styrene-divinylbenzene copolymer, in which the amino acid corresponding to the C-terminal of the desired peptide is Having α-COO
Α-amino group other than α-COOH group which the amino acid or peptide fragment has by binding via the H group, and then toward the amino acid N-terminal direction of the desired peptide The step of condensing and binding the functional group of 1) and the step of removing the protecting group of the amino group forming a peptide bond such as the α-amino group in the bound amino acid or peptide fragment are sequentially repeated. By extending the peptide chain to form a peptide chain corresponding to the desired peptide, then removing the peptide chain from the polymer, and removing the protecting group from the protected functional group. It is carried out by obtaining the peptide and then purifying it. Here, the elimination of the peptide chain from the polymer and the removal of the protective group are preferably carried out simultaneously using hydrogen fluoride, from the viewpoint of suppressing side reactions.
Further, it is effective to purify the obtained peptide by reverse phase liquid chromatography.

The salt of the peptide of the present invention can be prepared by utilizing a usual salt formation reaction.

As is clear from the test examples described below, the peptides of the present invention and salts thereof (hereinafter abbreviated as peptides) have TGF-β-like activity and low toxicity in toxicity tests. Has been confirmed.

From the above results, the peptides of the present invention are useful for treating fractures, wounds, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal disease, multiple sclerosis and the like. Further, the peptides of the present invention effectively suppress the rejection reaction after organ transplantation.

The peptides of the present invention reduce the symptoms of the aforesaid patients by administration to patients with fractures, wounds, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal disease, multiple sclerosis and the like. be able to.

The dose for the effective expression of peptides varies depending on the disease, the severity of the patient, the drug tolerance, etc., but is usually 0.01 μg / kg / day for adults.
2 g / kg, preferably 0.01 μg / kg to 20
It is 0 mg / kg.

The dosage form is preferably a solution obtained by dissolving peptides in a physiologically acceptable solution such as 5% glucose solution or physiological saline, and the solution is various pharmacologically acceptable solutions. It may contain an additive.

The method of administration includes intravenous administration, subcutaneous administration, intraperitoneal administration, intraarticular administration, transdermal administration and the like. Oral administration is also possible by encapsulating or liposome-forming peptides.

[0019]

EXAMPLES The present invention will be specifically described below with reference to examples. The present invention is not limited to these examples.

Example 1 Formula (4): Asn Pro Gly Ala Ser Ala Ala Pro Cys Cys
The peptide represented by Val Pro Gln Ala LeuGlu (SEQ ID NO: 4) was synthesized by the solid phase synthesis method using an automatic peptide synthesizer. That is, a styrene-divinylbenzene copolymer having 4- [N- (t-butoxycarbonyl) -γ-benzyl-L-glutamyloxymethyl] -phenylacetamidomethyl group at a ratio of 0.70 mmol / g (resin). Granular resin composed of [styrene and divinylbenzene constituent molar ratio: 99: 1] [PAM glutamic acid, t-Boc-L-Gl manufactured by Applied Biosystems, USA]
u (OBzl)] 0.1 mmol was used to sequentially couple amino acids toward the N-terminus of the peptide. In the binding reaction,
As amino acids, N ↑ α- (t-butoxycarbonyl) -L-glutamine [t-Boc glutamine], N- (t-butoxycarbonyl) -L-leucine [t-Boc leucine] manufactured by Applied Biosystems, Inc., USA. , N- (t-
Butoxycarbonyl) -L-proline [t-Boc proline], N- (t-butoxycarbonyl) -L-glycine [t-Boc glycine], N- (t-butoxycarbonyl)
-L-asparagine [t-Boc asparagine], N- (t
-Butoxycarbonyl) -O-benzyl-L-serine [t-Boc serine], N- (t-butoxycarbonyl)-
S- (p-methoxybenzyl) -L-cysteine [t-Bo
c cysteine], N- (t-butoxycarbonyl) -L
-Valine [t-Boc valine] and N- (t-butoxycarbonyl) -L-alanine [t-Boc alanine] are each 1
Mmol was used.

The obtained peptide was subjected to deprotection and desorption from the solid phase by using HF reactor type I manufactured by Peptide Institute Co., Ltd. The crude product was purified by a preparative high performance liquid chromatograph manufactured by Millipore Waters [Column: Deltapack C18 47 × 300 mm with Preppack 1000 pressure module]. The obtained purified peptide is a high performance liquid chromatograph for analysis LC6A manufactured by Shimadzu Corporation [Column: TSKgel OD manufactured by Toso Corporation.
S-80TM CTR, mobile phase: mixed solvent of acetonitrile and water containing 0.05% by volume of trifluoroacetic acid (acetonitrile concentration was changed from 5% by volume to 50% by volume in 30 minutes)], A single peak was shown at 18.8 min. The molecular weight of the purified peptide obtained by FAB mass spectrometry was 1527 (theoretical value: 1527.72).

Examples 2 to 6 and Comparative Example 1 Formula (5): Ala Ala Pro Cys Cys Val Pro Gln Ala Leu
Peptide represented by Glu Pro Leu Pro IleVal (SEQ ID NO: 5) (Example 2), formula (6): Ala Pro Glu Ala Se
r Ala Ser Pro Cys Cys Val Pro Gln Asp Leu Glu (SEQ ID NO: 6) (Example 3), Formula (7): Ala Ser Pro Cys Cys Val Pro GlnAsp Leu Glu
Peptide represented by Pro Leu Pro Ile Val (SEQ ID NO: 7) (Example 4), formula (8): Asn Pro Gly Ala Ser
Ala Ser Pro Cys Cys Val Ser Gln Asp Leu Glu Pro Le
u Thr Ile Leu (SEQ ID NO: 8) peptide (Example 5), formula (9): Asn Pro Gly Ala Ser Ala Se
r Pro Cys Cys Val Ser Gln AspLeu Glu Pro Leu Pro I
The peptide represented by le Leu (SEQ ID NO: 9) (Example 6), and formula (10): Gly Pro Cys Pro Tyr Ile Tr
The peptide represented by p Ser Leu Asp Thr Gln Tyr Ser (SEQ ID NO: 10) (Comparative Example 1) was synthesized by the same method as in Example 1.

In Example 2 and Example 4, 4- [N-
Styrene-divinylbenzene copolymer having a ratio of (t-butoxycarbonyl) -L-valyloxymethyl] -phenylacetamidomethyl group of 0.68 mmol / g (resin) [molar ratio of styrene and divinylbenzene: 99] [1] granular resin [PAM valine, t-Boc-L-Val manufactured by Applied Biosystems, USA]
0.1 mmol was used and in Example 3, 4- [N- (t-
Butoxycarbonyl) -γ-benzyl-L-glutamyloxymethyl] -phenylacetamidomethyl group was converted to 0.
Granular resin consisting of styrene-divinylbenzene copolymer [molar ratio of styrene and divinylbenzene: 99: 1] having a ratio of 70 mmol / g (resin) [PAM glutamic acid manufactured by Applied Biosystems, USA]
t-Boc-L-Glu (OBzl) 2] 0.1 mmol was used in Example 5.
And in Example 6, a styrene-divinylbenzene copolymer having 4- [N- (t-butoxycarbonyl) -L-leucyloxymethyl] -phenylacetamidomethyl group at a ratio of 0.68 mmol / g (resin). Granular resin consisting of [styrene and divinylbenzene compositional molar ratio: 99: 1] [P-manufactured by Applied Biosystems, USA, P
AM leucine, t-Boc-L-Leu] 0.1 mmol,
In Comparative Example 1, 4- [N- (t-butoxycarbonyl)-
Styrene-divinylbenzene copolymer having O-benzyl-L-seryloxymethyl] -phenylacetamidomethyl group in a ratio of 0.72 mmol / g (resin) [molar ratio of styrene and divinylbenzene: 99: 1] 0.1 mmol of a granular resin (PAM serine, t-Boc-L-Ser (Bzl), manufactured by Applied Biosystems, USA) was used.

As the amino acid, in addition to those used in Example 1, N- (t-butoxycarbonyl) -O- (2-bromobenzyloxycarbonyl) -L-tyrosine manufactured by Applied Biosystems, Inc. of the United States is used. [T-Boc tyrosine], N- (t-butoxycarbonyl) -L-isoleucine [t-Boc isoleucine], N- (t-butoxycarbonyl) -γ-benzyl-L-glutamic acid [t-Bo
c glutamic acid], N- (t-butoxycarbonyl)-
β-benzyl-L-aspartic acid [t-Boc aspartic acid], N ↑ α- (t-butoxycarbonyl) -NInd
-Formyl-L-tryptophan [t-Boc tryptophan] was used.

Deprotection and desorption from the solid phase were performed on each of the obtained peptides in the same manner as in Example 1 to purify the crude product. For each purified peptide, Table 1 shows the elution time in an analytical high performance liquid chromatograph and the molecular weight measurement results by FAB method mass spectrum.

[0026]

[Table 1]

Test Example 1 Growth inhibition test of concanavalin A-stimulated mouse spleen cells BALB / c mouse spleen cells were converted to concanavalin A: 3.
RPMI-1 contained at a ratio of μg / ml, 2-mercaptoethanol: 50 μM, fetal calf serum: 13%, respectively.
Dispersed in 640 medium, 96 cells at a rate of 5000 cells / well
It was dispensed into a well plate and cultured at 37 ° C. for 7 days in the presence of 7% CO ↓ 2. After culturing, the DNA of living cells was labeled with propidium iodide, and the fluorescence intensity was measured to count the number of living cells. 100 μg / m peptide
l and TGF-β were added immediately before concanavalin A stimulation to a concentration of 1 ng / ml. The decrease in the number of viable cells when the peptide or TGF-β was added was expressed as the inhibition rate, while the increase in the number of viable cells in the well to which only concanavalin A was added was compared to the well to which concanavalin A was not added. The results are shown in Table 2.

[0028]

[Table 2]

As shown in Table 2, the inhibition rate of TGF-β was 8
In contrast to 5%, the inhibition rates of the peptides obtained in Examples 1 to 6 are 60% to 73%, and it is clear that the peptides of the present invention exhibit TGF-β-like activity. is there.

Test Example 2 Colony formation test in soft agar 2.5 ng / ml EGF, 10% fetal bovine serum and 0.5%.
NRK-49F cells were seeded on a petri dish having a diameter of 10 cm at a rate of 1000 cells / dish in Eagle's MEM medium containing agar, and cultured at 37 ° C. for 7 days in the presence of 7% CO ↓ 2. Live cells were stained with Neutral Red and colony 1
The ratio of colonies having a diameter of 70 μm or more per 00 was determined. As a result, when the peptide obtained in Example 1 was added at a concentration of 300 μg / ml, 58% of the colonies were formed on average, and colony formation was significantly promoted as compared with the average of 33% of the control to which nothing was added. Was done.

[0031]

The peptides provided by the present invention are
It is effective in treating bone fractures, wounds, multiple sclerosis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal disease and the like, and can effectively suppress rejection after organ transplantation.

[0032]

[Sequence list]

SEQ ID NO: 1 Sequence length: 11 Sequence type: Amino acid Topology: Linear Sequence type: Peptide

SEQ ID NO: 2 Sequence length: 11 Sequence type: Amino acid Topology: Linear Sequence type: Peptide

SEQ ID NO: 3 Sequence length: 11 Sequence type: Amino acid Topology: Linear Sequence type: Peptide

SEQ ID NO: 4 Sequence length: 16 Sequence type: Amino acid Topology: Linear Sequence type: Peptide sequence Asn Pro Gly Ala Ser Ala Ala Pro Cys Cys Val Pro Gln Ala Leu Glu 1 5 10 15

SEQ ID NO: 5 Sequence length: 16 Sequence type: Amino acid Topology: Linear Sequence type: Peptide sequence Ala Ala Pro Cys Cys Val Pro Gln Ala Leu Glu Pro Leu Pro Ile Val 1 5 10 15

SEQ ID NO: 6 Sequence length: 16 Sequence type: Amino acid Topology: Linear Sequence type: Peptide sequence Ala Pro Glu Ala Ser Ala Ser Pro Cys Cys Val Pro Gln Asp Leu Glu 1 5 10 15

SEQ ID NO: 7 Sequence length: 16 Sequence type: Amino acid Topology: Linear Sequence type: Peptide sequence Ala Ser Pro Cys Cys Val Pro Gln Asp Leu Glu Pro Leu Pro Ile Val 1 5 10 15

SEQ ID NO: 8 Sequence length: 21 Sequence type: Amino acid Topology: Linear Sequence type: Peptide sequence Asn Pro Gly Ala Ser Ala Ser Pro Cys Cys Val Ser Gln Asp Leu Glu 1 5 10 15 Pro Leu Thr Ile Leu 20

SEQ ID NO: 9 Sequence length: 21 Sequence type: Amino acid Topology: Linear Sequence type: Peptide sequence Asn Pro Gly Ala Ser Ala Ser Pro Cys Cys Val Ser Gln Asp Leu Glu 1 5 10 15 Pro Leu Pro Ile Leu 20

SEQ ID NO: 10 Sequence length: 14 Sequence type: Amino acid Topology: Linear Sequence type: Peptide sequence Gly Pro Cys Pro Tyr Ile Trp Ser Leu Asp Thr Gln Tyr Ser 1 5 10

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location A61K 37/02 ACK ADA 8314-4C ADF C07K 99:00

Claims (3)

[Claims] 1. A general formula H-X ↑ 1-Ala-X ↑ 2-Pro-Cys-Cys-Val-X ↑ 3-
Gln-X ↑ 4-Leu-Glu-X ↑ 5-Y (In the formula, X ↑ 2 represents an amino acid residue selected from the group consisting of Ser and Ala, and X ↑ 3 is selected from the group consisting of Ser and Pro. X ↑ 4 represents an amino acid residue selected from the group consisting of Ala and Asp,
X ↑ 1 and X ↑ 5 are single bonds or Gly and Al, respectively.
a, Val, Arg, Asn, Ser, Phe, Pro, Leu, Glu,
It represents a peptide fragment consisting of 1 to 5 amino acid residues selected from the group consisting of Asp, Lys, Thr, His, Tyr, Nle and Ile, and Y represents a hydroxyl group or an amino group. )
And a peptide having TGF-β-like activity or a salt thereof. 2. A general formula H-X ↑ 6-A-X ↑ 7-Y (wherein A is the formula (1): Ala Ala Pro Cys Cys Val Pro.
Peptide fragment represented by Gln Ala Leu Glu (SEQ ID NO: 1), Formula (2): Ala Ser Pro Cys Cys Val ProGln Asp
Peptide fragment represented by Leu Glu (SEQ ID NO: 2) or formula (3): Ala Ser Pro Cys Cys Val Ser Gln Asp
Leu Glu (SEQ ID NO: 3) represents a peptide fragment, wherein X ↑ 6 and X ↑ 7 are a single bond or Gly,
Ala, Val, Arg, Asn, Ser, Phe, Pro, Leu, G
It represents a peptide fragment consisting of 1 to 5 amino acid residues selected from the group consisting of lu, Asp, Lys, Thr, His, Tyr, Nle and Ile, and Y represents a hydroxyl group or an amino group. ] The peptide or its salt according to claim 1, which is represented by 3. The following formula (4): Asn Pro Gly Ala Ser Ala Ala Pro Cys Cys
Val Pro Gln Ala Leu Glu (SEQ ID NO: 4), Formula (5): Ala Ala Pro Cys Cys Val Pro Gln Ala Leu
Glu Pro Leu Pro Ile Val (SEQ ID NO: 5), Formula (6): Ala Pro Glu Ala Ser Ala Ser Pro Cys Cys
Val Pro Gln Asp Leu Glu (SEQ ID NO: 6), Formula (7): Ala Ser Pro Cys Cys Val Pro Gln Asp Leu
Glu Pro Leu Pro Ile Val (SEQ ID NO: 7), Formula (8): Asn Pro Gly Ala Ser Ala Ser Pro Cys Cys
Val Ser Gln Asp Leu Glu Pro Leu Thr Ile Leu (SEQ ID NO: 8) or Formula (9): Asn Pro Gly Ala Ser Ala Ser Pro Cys Cys
The peptide or salt thereof according to claim 1, which is represented by Val Ser Gln Asp Leu Glu Pro Leu Pro Ile Leu (SEQ ID NO: 9).