WO1999015552A1 - Oligopeptide compounds - Google Patents

Abstract

Oligopeptide compounds having an oligopeptide residue represented by: -Met-Tyr-Pro-Pro-Pro-Tyr- or -Pro-Ser-His-Asn-Thr-Asp-Glu-Val; in particular, novel oligopeptide compounds useful as B7 inhibitors or compounds having a B7 inhibitory effect; a method for screening these compounds; and medicinal compositions and B7 inhibitors containing these compounds and applicable to the field of immunology (autoimmune diseases, allergy, rejection reaction in organ transplantation, bacterial infection, cancer, tumor, AIDS, etc.).

Description

 Specification

 Oligopeptide compounds Technical field

 The present invention relates to oligopeptide compounds. More specifically, the present invention relates to a novel oligopeptide compound useful as a B7 inhibitor. The present invention also relates to a compound having a B7 inhibitory action and a method for screening the same. Further, the present invention relates to a pharmaceutical composition and a B7 inhibitor containing the compound. It also relates to methods for inhibiting B7 and the use of these compounds for producing B7 inhibitors. Background art

 In recent years, excellent immunosuppressants such as FK-506 (Fujisawa Pharmaceutical) and cyclosporine have been developed and applied to organ transplants, autoimmune diseases, and the like. However, immunosuppressants such as FK-506 are non-antigen-specific, and their side effects such as nephrotoxicity have been regarded as a problem.

 By the way, recently, an antigen-specific signal via T cell receptor (TCR) alone is not enough to establish an immune response by T cell activation. signal) is now mandatory. And the B7 molecular family (eg, B7.1 (or CD80), B7.2 (or CD86), MB7.2) are the most important in T cell activation. It was found that these were costimulatory molecules. See, for example, Schwartz, RH, Cell, 57, pl073 (1989), Freeman, G.J. et al., J. Immun., 143, p2714 (1989).

Therefore, substances that inhibit the action of the B7 molecule family (referred to as B7 inhibitors) are expected to act as antigen-specific immunosuppressants, and research on B7 inhibitors has been conducted. B7 inhibitors include anti-B7 antibodies and CTLA4-Ig (CTLA4 is a molecule expressed on activated T cells, CTLA4-Ig is a fusion protein of CTLA4 and immunoglobulin ) Is only reported. See Finck, BK, Linsley, PS and Wofsy, D., Science, 265, pl225-1227 (1994). When. CTL A 4—Ig is under development by Bristol-Myers Squibb o

 In view of the above circumstances, the present inventors have conducted research on a B7 inhibitor having a smaller molecule, lower immunogenicity and higher tissue permeability than a conventional B7 inhibitor, and as a result, a novel o7 inhibitor has been obtained. The present invention has been completed by finding that a ligoptide compound has a B7 inhibitory action. That is, an object of the present invention is to provide an oligopeptide compound useful as a B7 inhibitor. Another object of the present invention is to provide a compound having a B7 inhibitory action and a screening method thereof. Furthermore, an object of the present invention is to provide a pharmaceutical composition and a B7 inhibitor containing the compound. Another object of the present invention is to provide a method for inhibiting B7 and the use of these compounds for producing a B7 inhibitor. Disclosure of the invention

 The gist of the present invention made to solve the above problems is

 ① Oligopeptide compound having an oligopeptide residue represented by -Met-Tyr-Pro-Pro-Pro-Tyr- or a salt thereof;

 ② The following general formula (1)

R, -X, -Met-Tyr-Pro-Pro-Pro-Tyr-X ₂ -R ₂ (1)

(Wherein represents N-terminal H or a substituent thereof, R ₂ represents C-terminal OH or a substituent thereof, and X and X ₂ each independently represent a single bond, an amino acid residue or a plurality of amino acids. This shows a peptide chain consisting of carboxylic acid.

 The oligopeptide compound or a salt thereof according to the above (1), which is represented by:

③ Χι is a single bond, -Lys-Val-Glu-Leu-, -Cys-Lys-Vatro Glu-Leu-, -Cys-Gly-, -Cys-Gly-Gly-, -Cys-Gly-Gly-Gly -Or-Cys-, X ₂ is a single bond, -Tyr-Leu -Gly-lie-, -Tyr-Leu-Gly- 1 le-Gly-Cys-, -Gly-Cys- or -Cys-, R, is The oligopeptide compound or a salt thereof according to the above (1), wherein H or acetyl group, and R ₂ is OH or NH ₂ ;

④-Pro-Ser-His-Asn-Thr-Asp-Glu-Vat-containing oligopeptide compound having an oligopeptide residue or a salt thereof; 一般 The following general formula (2)

 R -X -Pro-Ser-His-Asn-Thr-Asp-Glu-Val-X -R (2)

(Wherein the H or the substituents R ₃ is N-terminal, R ₄ represents OH or a substituent thereof at the C-terminus, to X ₃ and chi ₄ are each independently a single bond, an amino acid residue or a plurality 2 shows a peptide chain consisting of the amino acid of

The oligopeptide compound or a salt thereof according to the above (1), which is represented by:

⑥ chi ₃ is a single bond or - Glu- Ser- His-, X ₄ is a single bond or - Arg- Va Bok Thr- Val - L eu-, R ₃ is H or Asechiru group, R ₄ is OH or NH ₂ A certain oligopeptide compound or a salt thereof according to the above 1);

 ォ The oligopeptide compound or salt thereof according to any one of the above-mentioned ① to る こ と, which is a compound having a B7 inhibitory action;

⑧ medium containing a C 5 7 BL / 6 mouse-derived T cell, anti-CD 3 antibody, LPS activated B cells, the ³ H- thymidine and target drug were mixed, after cell culture, incorporated into said T cells A compound having a B7 inhibitory action, which is screened using a system for analyzing the degree of inhibition of the costimulatory reaction of the target drug by measuring the amount of ³ H-thymidine obtained;

 医 薬 A pharmaceutical composition comprising the oligopeptide compound according to any one of the above items ① to 、, the compound having a B7 inhibitory activity or a salt thereof described in the above item ⑧, and a pharmaceutically usable carrier. ;

 ォ The oligopeptide compound according to any one of the above ① to ⑦, a B7 inhibitor comprising as an active ingredient a compound having a B7 inhibitory activity or a salt thereof according to the above ⑧;

阻 害 Inhibiting B7, comprising administering to a patient an effective amount of the oligopeptide compound according to any one of the above ① to 、, the compound having a B7 inhibitory activity or a salt thereof according to the above ⑧. how to;

 使用 Use of the oligopeptide compound according to any one of the above-mentioned ⑦ to 、, a compound having a B7 inhibitory activity described in ⑧ above, or a salt thereof, for producing a B7 inhibitor;

⑬ medium containing a C 5 7 BL / 6 mouse-derived T cell, anti-CD 3 antibody, LPS activated B cells, ³ H- mixed thymidine and target drug, after cell culture, the T fine A method of screening for a compound having a B7 inhibitory action (target drug) by using a system for analyzing the degree of inhibition of the costimulatory reaction of the target drug by measuring the amount of ³ H-thymidine incorporated into the cells;

⑭ T cells (1 ~ 2) X 1 0 5 cells Z Ueru,? (3) Activated 8 cells are used in an amount of (1 to 40) × 10 ⁴ cells / μl, anti-CD3 antibody is used in an amount of about 1 ng / m 1, and culture days are 1 to 3 days. A method for screening a compound having B7 inhibitory activity (target drug) described in the above;

In

 (Embodiment of the invention)

 The present invention

 -Met- Tyr- Pro- Pro- Pro-Tyr- or

 -Pro-Ser-His-Asn-Thr-Asp-Glu-Val--an oligopeptide compound having an oligopeptide residue or a salt thereof, which is pharmacologically acceptable And salts of inorganic or organic acids such as hydrochloride, sulfate, phosphate, acetate, citrate, methanesulfonate, sodium salt, potassium salt, calcium salt, ammonium salt. Examples thereof include inorganic bases and organic base addition salts such as salts and pyridin salts.

 The oligopeptide compound of the present invention includes various compounds as long as it is the above-mentioned oligonucleotide having an amino acid sequence, and any amino acid or any amino acid or A plurality of arbitrary amino acid peptide chains may be bonded, and the N-terminal amino group and / or the C-terminal carboxy group of these oligopeptides may have a substituent; and It may be a cyclic oligopeptide having an N-terminal and a C-terminal bonded, and when the oligopeptide contains two or more cysteines, those cysteines are linked by a disulfide (—S—S—) bond. It may be cyclized. The number of amino acids of the oligopeptide compound of the present invention is about 6 to 25, preferably about 6 to 20, and more preferably about 6 to 10. A preferred compound of the oligopeptide compound of the present invention has the following general formula (1) or general formula (2)

R r X Met- Tyr- Pro-Pro- Pro- Tyr- X ₂ -R ₂ (1) _{(Wherein, 1 ^, 1 ^ 2,} X, and X ₂ are as defined above)

 R -X -Pro-Ser-His-Asn-Thr-Asp-Glu-Val-X -R (2)

(Wherein, R ₃ , R ₄ , X ₃ and Χ ₄ are the same as above)

It is represented by

In the above general formulas (1) and (2), ₁ and ₂ and ₃ and ₄ are the same or different and are each a single bond, an amino acid residue or a peptide chain composed of a plurality of amino acids, and X and chi Examples ₂ and chi peptide chain composed of ₃ and chi ₄ amino acid residue or a plurality of amino acids, to select a peptide chain of arbitrary amino acid residue or a plurality of any amino acid Possible force X, preferably -Lys-Val-Glu-Leu-, -Cys-Lys-Val-Glu-Leu-, -Cys-Gly-, -Cys-Gly-Gly-, -Cys-Gly- Gly-Gly-, -Cys-, etc. are exemplified. As X ₂ , -Tyr-Leu-Gly-1le-, -Tyr-Leu-Gly-lie-Gly-Cys-, -G-Cys-, -Cys - the like. Examples of the X ₃ - Glu-Ser- His- the like. Examples of the X ₄ - Arg-Va Bok Thr- Va Bok Leu- the like.

R and R ₃ represent N-terminal H or a substituent thereof. Examples of the substituent include an acyl group (for example, an alkanol group such as acetyl (Ac), propionyl, butyryl, lauroyl, benzoyl, Aromatic acyl groups such as naphthoyl, heterocyclic acyl groups such as furoyl, tenyl and nicotinyl), alkyl groups such as methyl, ethyl and propyl, and aralkyl groups such as benzyl and benzhydryl. The substituent may be substituted with, for example, an alkyl group, a hydroxyl group, a nitro group, a halogen, or the like.

R ₂ and R _{4 each} represent C-terminal OH or a substituent thereof. Examples of the substituent include an amide group and an ester group. More specifically, R ₂ includes, for example, amino, Examples thereof include an amino group which may have a substituent such as alkylamino (for example, methylamino and ethylamino), benzylamino and the like, and an alkoxy group such as methoxy, ethoxy, butoxy and benzyloxy.

In this specification, H at the N-terminus refers to の of the free α-amino group of the N-terminal amino acid residue, and ΟΗ at the C-terminus refers to the free growth of the C-terminal amino acid residue. Refers to the base ΟΗ. The oligopeptide compound of the present invention can be produced by a chemical synthesis method or by a genetic engineering technique.

 Chemical synthesis methods include known peptide synthesis methods, for example, a method in which amino acids are coupled stepwise from the C-terminus or a method in which amino acids are coupled stepwise from the N-terminus, and oligopeptides having a partial sequence. Examples of the method include a binding method, a liquid phase method or a solid phase method, manual synthesis, and synthesis using an automatic synthesizer.

 In addition, as a genetic engineering technique, DNA having a base sequence corresponding to the target oligopeptide is synthesized, and the DNA is incorporated into an appropriate expression system, expressed, and produced as a recombinant substance. Such a genetic engineering technique is already known and can be performed according to a conventional method.

Further, the compound having a B7 inhibitory activity of the present invention is a compound that can be selected in a screening system described in Experimental Examples described later, and more specifically, a medium containing T cells derived from C57BL / 6 mouse. the anti-CD 3 antibody, teeth 8 activation 8 cells were mixed ³ H- thymidine及beauty target drug, after cell culture, by measuring ³ H- thymidine amount incorporated into said T cells, the subject It can be obtained by a screening method using a system for analyzing the degree of inhibition of the costimulatory reaction of a drug. Here, the target drug includes an arbitrary compound that is to be screened, and includes an oligonucleotide compound other than the oligonucleotide compound having the above-mentioned structure and other arbitrary compounds.

The anti-CD3 antibody and LPS-activated B cells used in the above-mentioned screening system can be prepared according to the method described in the literature (Int. J. Cancer 70, 1-8, 1997). . The T cells used preferably, (1~ 2) X 1 0 5 cells Z Ueru, more preferably 1 X 1 0 ⁵ cells Z Ueru about, LPS activated B cells are preferably, (1 - 4 0) X 1 0 ⁴ cells / Uweru, more preferably 1 X 1 0 ⁴ cells / Uweru about, the anti-CD 3 antibody preferably adjusted to a concentration of about 1 GZm 1. The culturing time is preferably about 1 to 3 days, more preferably about 2 days. The use concentration of the target drug is preferably about 100 to 300. ^The amount of ³ H-thymidine incorporation can be measured by a liquid scintillation 'counting method or a bio-imaging analyzer (BAS) method according to a conventional method.

By selecting drugs with high inhibitory effect on costimulatory activity in the above-mentioned screening system Thus, a compound having a B7 inhibitory action can be obtained. The compound having a B7 inhibitory action selected by the method using such a screening system may be an oligopeptide compound, but may be another type of compound. The oligonucleotide compound obtained by the above screening method is not limited to the oligonucleotide compound whose structure is specified, but includes any compound having a B7 inhibitory action.

 The oligopeptide compound having a specific structure of the present invention, the compound having a B7 inhibitory action or a salt thereof (hereinafter, referred to as “the compound of the present invention”) may be used alone or in combination of a plurality of types to prepare a normal preparation. A pharmaceutical composition can be obtained by mixing a chemically available carrier. Further, the compound of the present invention can be administered to a patient orally or parenterally in the form of the pharmaceutical composition. The dose can be appropriately adjusted according to the patient's condition, sex, weight, and the like. Specifically, about 0.001 to 100 mg per day for a patient is exemplified as an effective amount. BEST MODE FOR CARRYING OUT THE INVENTION

 Examples and experimental examples are described in order to explain the present invention in more detail, but the present invention is not limited to these.

 Example 1

A c -Met-Tyr-Pro- Pro-Pro-Tyr- NH 2 (C 4 o H 53 N 7 0 9 S = 8 0 7. 9 7, compounds of SEQ ID NO 1, "Sequence Listing Furitekisu Bok" : The N-terminal amino group is acetylated, and the C-terminal carboxy group is amidated.)

The protected form of the oligopeptide was synthesized using a peptide synthesizer (device name: PS SM-8, manufactured by Shimadzu Corporation). That is, the starting resin used was TGS-RAM (0.2 mmol / g), 100 mg Fmoc / HBTU liquid method. Subsequently, final deprotection of the obtained protected product was performed. The conditions were room temperature and 5 hours using reagent K. The prepared crude product was fractionated and purified by HP LC. The conditions are reversed phase C _{l 8} column, elution _{0. 5% CH 3 CN / 0} . 0 5% TF A gradient of aqueous solutions, detection A _23. Was used.

The compounds of Examples 2 to 4 were synthesized in the same manner as in Example 1. Example 2

A c- Lys- Va Bok Glu- Leu- Met- Tyr- Pro- Pro- Pro- Tyr- NH 2 (C e 2 H 9 2 N. 2 01 5 S = 1 2 7 7. 5 6, SEQ ID NO: 2 , "Sequence listing free text": N-terminal amino group is acetylated, C-terminal carboxy group is amidated o)

 Example 3

A c- Met- Tyr- Pro- Pro- Pro- Tyr Tyr- Leu- Gly- 1 le- NH 2 (C e 3 H 8 7 N,, 0, 4 S = 1 2 5 4. 5 1, SEQ ID NO: Compound 3, "Sequence List Free Text": N-terminal amino group is acetylated, C-terminal carboxy group is amidated o)

 Example 4

A c— Lys-Va Glu- Leu- Met- Tyr- Pro- Pro- Pro- Tyr- Tyr- Leu- Gly- lie— NH ₂ (C 85 H, 26 N. 17 ₂ 4.09, sequence No. 4 compound, “Sequence List Free Text”: N-terminal amino group is acetylated, and C-terminal carboquine group is amidated.)

 Example 5

 S S

A c -Cys-et-Tyr-Pro-Pro-Pro-Tyr-Cys-NHs (C ₄₆ H _s , N ₉₀ ,, S ₃ = 10 1 2.2 2, compound of SEQ ID NO: 5, Column list free text: ： The amino group at the Ν-terminal is acetylated, the carboxy group at the C-terminal is amidated, and the Cys at the Ν-terminal and the Cys at the C-terminal are linked by one S_S—. The synthesis of

The protected oligopeptide was synthesized using a peptide synthesizer (device name: PS SM-8, manufactured by Shimadzu Corporation). The starting resin used was TGS-RAM (0.2 mmo 1 /), 100 mg Fmo cZHBTU liquid method. Subsequently, final deprotection of the obtained protected product was performed. The conditions were room temperature and 5 hours using reagent K. The prepared deprotected product (dithiol product) was subjected to an oxidation reaction with potassium ferricyano under high dilution. The synthesized cyclic compound was fractionated and purified by HPLC. The conditions were reversed-phase _C18 column, elution was 0.05% CH ₃ CN / 0.05% TFA water. Gradient method of the solution, detection A _23. Was used.

 The compound of Example 6′13 was synthesized in the same manner as in Example 5.

 Example 6

 S ■ S

A c - Cys- Lys-Va Bok Glu- Leu- Met- Tyr- Pro- Pro- Pro- Tyr- Cys- NH 2 (CeeH.ooN 1 4 0, 7 S = 1 4 8 1. 8 0, SEQ ID NO: Compound 6, “Sequence List Free Text”: N-terminal amino group is acetylated, C-terminal carboxy group is amidated, and N-terminal Cys and C-terminal Cys are —S — Linked by S—.)

 Example 7

 S S

A c--Cys- Met- Tyr- Pro- Pro- Pro- Tyr- Tyr- Leu- Gly_lle- Gly- Cys- NH ₂ (C ₇₁ H _{9 8} N ₁₄ 0, 7 S 3 = 1 5 15.8 Compound of SEQ ID NO: 7, “Sequence List Free Text”: N-terminal amino group is acetylated, C-terminal carboquine group is amidated, and N-terminal Cys and C-terminal Cys are They are linked by one S—S—.)

 Example 8

 S -S

A c-Cys- Lys- Vatro Glu- Leu- Met- Tyr- Pro- Pro- Pro- Tyr- Tyr- Leu-Gly-1 le-Gly- Cys-NH ₂ (C ₉₃ H ₁₃₇ N _{I 9 23} S ₃ = 1 9 8 5. 39, Compound of SEQ ID NO: 8, “Sequence List Free Text”: N-terminal amino group is acetylated, and C-terminal carboxy group is amidated. In addition, N-terminal Cys and C-terminal Cys are linked by —S—S. Example 9

 S S

A c -Cys- Gly- Met- Tyr- Pro- Pro- Pro- Tyr- Cys- NH 2 (C 4 a H 6 4 io 0, 2 S 3 = 1 0 6 9. 2 7, compounds of SEQ ID NO: 9 , “Sequence List Free Text”: N-terminal amino group is acetylated, C-terminal carboxy group is amidated, and N-terminal Cys and C-terminal Cys are —S— Linked by S—)

 Example 10

 S S

A c -Cys-Gly-Gly-et-Tyr-Pro-Pro-Pro-Tyr-Cys-NH ₂ (C ₅ ο Η ₆ τ N,, 0, ₃ S ₃ = 1 1 2 6.32, sequence Compound No. 10 “Sequence List Free Text”: N-terminal amino group is acetylated, C-terminal carboxy group is amidated, and N-terminal Cys and C-terminal Cys are — S— S— are linked.) Example 11

 S S

A c -Cys- Gly- Gly-Gly- Met- Tyr- Pro- Pro- Pro- Tyr- Cys- NH ₂ (C ₅₂ H ₇ oN, ₂₀ , 4 S 3 = 1 1 8 3.37, sequence No. 11 compound, “Sequence List Free Text”: N-terminal amino group is acetylated, C-terminal carboxy group is amidated, N-terminal Cys and C-terminal Cys Is connected by one S—S—o)

 Example 1 2

A c -Pro-Ser-His-Asn-Thr-Asp-Glu-Val-NH ₂ (C 3 a H ₅ s N, 20, ₆ = 9 3 8.966, the compound of SEQ ID NO: 12; Column list free text ": ΝThe amino group at the terminal is acetylated, and the carboxy group at the C terminal is amidated.)

 Example 13

A c -Glu-Ser-His-Pro-Ser-His-Asn-Thr-Asp-Glu-Val-Arg-Val-Thr-Val-Leu-N H ₂ (C 8.H1 ₂ TN ₂₃ 029 = 1 8 87.0 03, the compound of SEQ ID NO: 13; Lee text ": The amino group at the N-terminus is acetylated, and the carboxyl group at the C-terminus is amided. )

 Experimental example 1

Measurement of B7 inhibitory activity (1)

 B7 inhibitory activity was determined by measuring the inhibitory effect of the test drug on the proliferation of T cells by anti-CD3 monoclonal antibody and LPS-activated B cells (activated B cells expressing B7). .

That, C 5 7 BL / 6 mouse-derived T cells (1 X 1 0 ⁵ cells) anti CD 3 antibody (1 ng / m 1) and LPS-activated B cells (1 X 1 0 ⁴ pieces) in 2 days Stimulation and costimulation activity were measured by ³ H-thymidine incorporation. A similar analysis was performed in the presence of the test drug, and the B7 inhibitory activity was evaluated based on how much the test drug inhibited the costimulatory response. The concentration of the test drug was 300 μM, and the amount of ^{3 3-} thymidine was 2 nC i. Radioactivity was measured by liquid scintillation 'counting method or bio-imaging analyzer (BAS) method. Table 1 shows the results. The anti-CD3 monoclonal antibody and LPS-activated B cells were prepared according to the method described in the literature (Int. J. Cancer 70, 1-8, 1997).

 table 1

 Experimental example 2

The measurement was carried out according to Experimental Example 1 except that the concentration of the test drug was set at 100 / M (in a DMS concentration of 0 to 25%). Table 2 shows the results. Table 2

 As shown in the above results, the compound of the present invention has reduced costimulatory activity,

It was found to have B7 inhibitory action.

 Experiment 3

 In order to confirm that the inhibitory activity of the compound of the present invention is B7-specific, the B7 inhibitory activity was measured in the presence of an anti-CD288 monoclonal antibody (1 g Zm1) according to Experimental Example 2. went. If the inhibitory activity of the compound of the present invention is B7-specific, the presence of the anti-CD28 monoclonal antibody will restore the costimulatory activity. As a result of this test, the inhibitory effect of the compound of the present invention was completely released by the anti-CD28 monoclonal antibody. In addition, it was similarly released when a 5-fold amount of LPS-activated B cells was used. That is, it was found that the B7 inhibitory action of the compound of the present invention was B7-specific.

 Formulation Example 1

 The compound of the present invention (the compound of Example 2) was mixed with 1 g of lactose to prepare a powder.

Formulation Example 2 1 O mg of the compound of the present invention (the compound of Example 2) was added directly to fine granules (consisting of magnesium metasilicate, corn starch and lactose, manufactured by Fuji Chemical Co., Ltd.) 110 mg, crystalline cellulose 60 mg, CMC Tablets were prepared by mixing with 18 mg of calcium and 2 mg of magnesium stearate, followed by tableting.

 Formulation Example 3

 10 mg of the compound of the present invention (the compound of Example 2) was dissolved in 10 ml of physiological saline to prepare an injection. Industrial applicability

 Since the compound of the present invention can have a B7 inhibitory effect, it is expected to be used in the immune field. That is, it can be applied to autoimmune diseases, allergies, rejection at the time of organ transplantation, bacterial infection, cancer, tumor, AIDS, and the like. In particular, since the oligopeptide compound of the present invention has a lower molecular weight than conventional protein-based inhibitors (anti-B7 antibody, CTLA4-Ig, etc.), it has reduced immunogenicity and tissue permeability. Improvement and reduction of side effects can be achieved.

Claims

The scope of the claims 1. -Met-Tyr-Pro-Pro-Pro-Tyr- An oligopeptide compound having an oligopeptide residue or a salt thereof.  2. The following general formula (1) R, -X, -Met-Tyr-Pro-Pro-Pro-Tyr-X ₂ -R ₂ (1) (Wherein, R, represents N-terminal H or a substituent thereof, R ₂ represents C-terminal OH or a substituent thereof, and X and X ₂ each independently represent a single bond, an amino acid residue or a plurality thereof. 2 shows a peptide chain consisting of the amino acid of The oligopeptide compound or a salt thereof according to claim 1, which is represented by the following formula: 3.X is a single bond, -Lys-Val-Glu-Leu-, -Cys-Lys-Val-Glu-Leu-, -Cys-Gly-, -Cys-Gly-Gly-, -Cys-Gly-Gly -Gly- or-Cys-, X ₂ is a single bond, -Tyr- Leu-Gly-lie-, -Tyr- Leu- Gly- 1 le- Gly- Cys-,-Gly- Cys-or-Cys-, R 3. The oligopeptide compound or a salt thereof according to claim ₂ , wherein is an H or acetyl group, and R ₂ is OH or NH ₂ .  4. An oligopeptide compound having an oligopeptide residue represented by -Pro-Ser-His-Asn-Thr-Asp-Glu-Val- or a salt thereof.  5. The following general formula (2)  R -X -Pro-Ser-His-Asn-Thr-Asp-Glu-Val-X -R (2) (Wherein the H or the substituents R ₃ is N-terminal, R ₄ represents OH or a substituent thereof at the C-terminus, to X ₃ and chi ₄ are each independently a single bond, an amino acid residue or a plurality 2 shows a peptide chain consisting of the amino acid of  The oligopeptide compound or a salt thereof according to claim 4, which is represented by the formula: 6. chi ₃ is a single bond or - Glu-Ser- His-, X ₄ is a single bond or - Arg- Val- Thr- Val-L eu- , R 3 is H or Asechiru group, R ₄ is OH or NH ₂ 6. The oligopeptide compound or a salt thereof according to claim 5, which is:  7. The oligopeptide compound or a salt thereof according to any one of claims 1 to 6, which is a compound having a B7 inhibitory action. 8. In the medium containing T cells derived from C57BLZ6 mice, add anti-CD3 antibody, LPS After the activated B cells, ³ H-thymidine and the target drug are mixed, and the cells are cultured, the amount of ³ H-thymidine incorporated into the T cells is measured to determine the degree of inhibition of the co-stimulatory reaction of the target drug. A compound having a B7 inhibitory action, which is screened using the system to be analyzed.  9. A pharmaceutical comprising the oligopeptide compound according to any one of claims 1 to 7, the compound having a B7 inhibitory action according to claim 8, or a salt thereof, and a pharmaceutically usable carrier. Composition.  10. A B7 inhibitor comprising the oligopeptide compound according to any one of claims 1 to 7, the compound having a B7 inhibitory action according to claim 8 or a salt thereof as an active ingredient.  11. An effective amount of the oligopeptide compound according to any one of claims 1 to 7, the compound having a B7 inhibitory action according to claim 8, or a salt thereof, is administered to the patient. How to inhibit the B7.  12. An oligopeptide compound according to any one of claims 1 to 7, a compound having a B7 inhibitory activity or a salt thereof according to any one of claims 1 to 7 for producing a B7 inhibitor. use.  1 3. Anti-CD3 antibody, LP in medium containing T cells derived from C57BL / 6 mouse S-activated B cells, ³ H-thymidine and target drug are mixed, and after cell culture, the amount of ³ H-thymidine incorporated into the T cells is measured to determine the degree of inhibition of the target drug's costimulatory reaction. A method of screening for a compound having a B7 inhibitory action (target drug) using a system for analyzing B7. 1 4. T cells (1~2) X 1 0 ⁵ cells / © Le, teeth 8 activation 8 cells (1 ~4 0) X 1 0 4 cells Z Uweru, anti CD 3 antibody of about 1 g / 14. The method for screening for a compound having B7 inhibitory activity (target drug) according to claim 13, wherein the compound is used in an amount of m1 and the culture period is 1 to 3 days.