Peptide, pharmaceutically acceptable salt thereof, and pharmaceutical composition

Abstract

This peptide, or a pharmaceutically acceptable salt thereof, contains a substructure having an amino acid sequence selected from the group consisting of (1) and (2). (1) Amino acid sequence represented by formula (I): RYRYYGHNLIAYGFY (SEQ ID NO: 1); (2) Amino acid sequence represented by formula (I) with 1 to 6 amino acids substituted, where, when the arginine at the N terminus is defined as the first amino acid residue, the first amino acid residue is optionally substituted with a basic amino acid other than arginine and histidine; the second amino acid residue is optionally substituted with an aromatic amino acid other than tyrosine and histidine; the third amino acid residue is optionally substituted with a basic amino acid other than arginine and histidine; the fourth amino acid residue is optionally substituted with an aromatic amino acid other than tyrosine and histidine; the fifth amino acid residue is optionally substituted with an aromatic amino acid other than tyrosine and histidine or an amino acid containing a hydroxy group; the sixth amino acid residue is optionally substituted with alanine or an analog thereof, or a glycine analog; the seventh amino acid residue is optionally substituted with an amino acid other than cysteine, lysine, proline, arginine, threonine, valine, and tryptophan; the eighth amino acid residue is optionally substituted with aspartic acid, glycine, tyrosine, phenylalanine, serine, histidine, glutamic acid, glutamine, alanine, leucine, or analogs thereof, or an asparagine analog; the ninth amino acid residue is optionally substituted with an amino acid other than glycine, proline, and tryptophan; the tenth amino acid residue is optionally substituted with a branched chain amino acid other than isoleucine; the eleventh amino acid residue is optionally substituted with an amino acid other than glycine, proline, and tryptophan; the twelfth amino acid residue is optionally substituted with a tyrosine analog or a phenylalanine analog; the thirteenth amino acid residue is optionally substituted with alanine or an analog thereof, or a glycine analog; the fourteenth amino acid residue is optionally substituted with histidine, leucine, tyrosine, tryptophan, or analogs thereof, or a phenylalanine analog; and the fifteenth amino acid residue is optionally substituted with an aromatic amino acid other than tyrosine and histidine.

Description

Peptides, pharmaceutically acceptable salts thereof, and pharmaceutical compositions

[0001] This invention relates to peptides, pharmaceutically acceptable salts thereof, and pharmaceutical compositions, etc.

[0002] Atopic dermatitis is a chronic skin disease that develops when the skin's barrier function is impaired for some reason, allowing external allergens and irritants to penetrate the skin. The invasion of allergens causes a specific immune system to overreact, leading to increased production of inflammatory cytokines. Therefore, a typical symptom of atopic dermatitis is unbearable itching. Patients can fall into a vicious cycle where scratching, damaging their own skin, worsens the symptoms.

[0003] Studies have suggested that oncostatin M (OSM), a type of IL-6 family cytokine, and its receptor, the oncostatin M receptor (OSMR), are involved in the mechanism of itching in atopic dermatitis.

[0004] Specifically, it has been suggested that oncostatin M binds to oncostatin M receptors, triggering itching signals, and research into this is ongoing. Furthermore, antibody preparations targeting oncostatin M receptors are being developed for the treatment of atopic dermatitis.

[0005] For example, Patent Document 1 discloses a monoclonal antibody against the oncostatin M-specific receptor beta subunit. Patent Document 1 also discloses that such an antibody is effective in immunotherapy for patients with atopic dermatitis.

[0006] Non-patent document 1 discloses the efficacy of vixarelimab, a monoclonal antibody against oncostatin M receptor beta, against prurigo nodularis.

[0007] Non-patent document 2 discloses that KPL-716, a monoclonal antibody against the oncostatin M receptor beta, can inhibit the induction of monocyte chemotactic protein (MCP)-1 by oncostatin M. Non-patent document 2 also discloses that such an antibody may be applicable to the treatment of inflammatory skin diseases.

[0008] International Publication No. 2013 / 168829

[0009] Sofen H, et. al., eClinicalMedicine. 2023 Feb 3, 57, 101826. doi: 10.1016 / j.eclinm.2023.101826.Richards CD, et. al., Acta Derm. Venereol. 2020 Jul 2, 100 (14), adv00197(5760). doi: 10.2340 / 00015555-3505.

[0010] However, although antibody preparations have high target specificity, they are generally administered by intravenous injection, which can lead to systemic side effects. Therefore, there is a need for a drug that can be applied locally and specifically binds to the oncostatin M receptor (OSMR). Accordingly, the present invention aims to provide a novel substance that targets the oncostatin M receptor (OSMR).

[0011] As a result of diligent research by the inventors, we discovered that peptides having a specific sequence can bind specifically and with high affinity to OSMR and inhibit OSM signaling, thus completing the present invention.

[0012] In other words, the present disclosure includes the following embodiments: [1] A peptide or a pharmaceutically acceptable salt thereof comprising a substructure having an amino acid sequence selected from the group consisting of (1) to (3) below, or (1) and (2). (1) An amino acid sequence represented by the following formula (I): RYRYYGHNLIAYGFY (I) (Sequence ID 1) (2) An amino acid sequence in which 1 to 6 amino acids are substituted in the amino acid sequence represented by the above formula (I), with arginine at the N-terminus being the first amino acid residue, the first amino acid residue may be substituted with a basic amino acid other than arginine and histidine, the second amino acid residue may be substituted with an aromatic amino acid other than tyrosine and histidine, the third amino acid residue may be substituted with a basic amino acid other than arginine and histidine, the fourth amino acid residue may be substituted with an aromatic amino acid other than tyrosine and histidine, the fifth amino acid residue may be substituted with an aromatic amino acid other than tyrosine or an amino acid containing a hydroxyl group, and the sixth amino acid residue may be substituted with alanine or its analogue, or a glycine analogue. The seventh amino acid residue may be substituted with an amino acid other than cysteine, lysine, proline, arginine, threonine, valine, and tryptophan; the eighth amino acid residue may be substituted with aspartic acid, glycine, tyrosine, phenylalanine, serine, histidine, glutamic acid, glutamine, alanine, leucine, or their analogues, or an asparagine analogue; the ninth amino acid residue may be substituted with an amino acid other than glycine, proline, and tryptophan; the tenth amino acid residue may be substituted with a branched-chain amino acid other than isoleucine; the eleventh amino acid residue may be substituted with an amino acid other than glycine, proline, and tryptophan; the twelfth amino acid residue may be substituted with a tyrosine analogue or a phenylalanine analogue; the thirteenth amino acid residue may be substituted with alanine, its analogue, or a glycine analogue.(3) An amino acid sequence having 80% or more identity with the amino acid sequence represented by formula (I) above. [2] In the amino acid sequence of (2) above, the first amino acid residue may be replaced with an arginine analog, the second amino acid residue may be replaced with tryptophan or an analog thereof, an phenylalanine analog, or an arginine analog, the third amino acid residue may be replaced with an arginine analog, the fourth amino acid residue may be replaced with an phenylalanine analog, or an arginine analog, the fifth amino acid residue may be replaced with an arginine analog or an arginine analog, the sixth amino acid residue may be replaced with an arginine analog. The seventh amino acid residue may be substituted with asparagine, aspartic acid, glycine, glutamine, serine, tyrosine, glutamic acid, isoleucine, alanine, or their analogues, or an analogue of histidine; the eighth amino acid residue may be substituted with glycine, or its analogue, or an analogue of asparagine; the ninth amino acid residue may be substituted with glutamine, glutamic acid, valine, isoleucine, lysine, arginine, asparagine, histidine, or their analogues, or an analogue of leucine; the tenth amino acid residue may be substituted with valine, or its analogue, or an analogue of isoleucine; the eleventh amino acid residue may be substituted with threonine, serine, lysine, glutamine, leucine, asparagine, arginine, valine, histidine, aspartic acid, isoleucine, or their analogues, or an analogue of alanine; the thirteenth amino acid residue may be substituted with an analogue of glycine. The 14th amino acid residue may be substituted with tyrosine, its analogue, or a phenylalanine analogue.The 15th amino acid residue may be replaced with an analog of tyrosine or an analog of phenylalanine, the peptide according to [1], or a pharmaceutically acceptable salt thereof. [3] A peptide, or a pharmaceutically acceptable salt thereof, comprising a partial structure having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to SEQ ID NOs: 21. [4] A cyclic peptide, wherein the partial structure is included in the cyclic structure, the peptide according to any one of [1] to [3], or a pharmaceutically acceptable salt thereof. [5] The partial structure contains an aromatic amino acid on the N-terminal side, contains an amino acid having a sulfhydryl group on the C-terminal side relative to the aromatic amino acid located on the N-terminal side of the partial structure, and the aromatic amino acid on the N-terminal side and the amino acid having the sulfhydryl group are bonded to form a cyclic structure, the peptide according to [4], or a pharmaceutically acceptable salt thereof. [6] The peptide according to [4], or a pharmaceutically acceptable salt thereof, wherein the peptide is represented by formula (II). (In the formula (II), partial structure represents the partial structure, and X ｒ , １ , ２ , １ , １ , ２ , ｒ , , １ , ２ , , and Xaa are each independently an amino acid, and X ２ is OH, NH ２ , or (Xaa') ｒ (Xaa' is an amino acid independent of the X １ and Xaa), n and m are each independently an integer from 0 to 5, and r is an integer from 1 to 20.) [7] In the formula (II), X １ is an aromatic amino acid, and n and m are 0, the peptide according to [6], or a pharmaceutically acceptable salt thereof. [8] In the formula (II), X １ is tryptophan, n and m are 0, X ２ is (Xaa') ｒ , r is 1, and Xaa' is glycine, the peptide according to [6], or a pharmaceutically acceptable salt thereof. [9] The peptide according to [4], or a pharmaceutically acceptable salt thereof, wherein the peptide is represented by formula (III). (In formula (III) above, partial structure represents the partial structure, X ２ OH, NH ２ , or (Xaa') ｒ (where Xaa' is an amino acid, and r is 1.)

[10] The peptide according to any one of [1] to [9], or a pharmaceutically acceptable salt thereof, wherein the number of amino acid residues forming the peptide is 15 to 30.

[11] The peptide according to any one of [6] to [9], or a pharmaceutically acceptable salt thereof, wherein the partial structure is an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to SEQ ID NOs: 21.

[12] A peptide or a pharmaceutically acceptable salt thereof comprising any of the following structures. (However, in the above structure, n means D-Asn, d means D-Asp, X ２ OH, NH ２ , or (Xaa') ｒ (Xaa' is an amino acid), and r is 1.)

[13] X ２ (Xaa') ｒ (Xaa' is an amino acid), and the above (Xaa') ｒA peptide according to any one of [6] to

[12] , wherein the N-terminus of is bonded to the carbonyl group of formula (II), or a pharmaceutically acceptable salt thereof.

[14] A peptide according to any one of [1] to

[13] , or a pharmaceutically acceptable salt thereof, that binds to the oncostatin M receptor.

[15] A peptide according to any one of [1] to

[13] , or a pharmaceutically acceptable salt thereof, having OSM signal inhibitory activity. [15-1] A peptide according to any one of [1] to

[13] , or a pharmaceutically acceptable salt thereof, having OSM signal and / or IL-31 signal inhibitory activity.

[16] A pharmaceutical composition comprising a peptide according to any one of [1] to

[15] or [15-1], or a pharmaceutically acceptable salt thereof.

[17] The pharmaceutical composition according to

[16] , used for the treatment or prevention of atopic dermatitis.

[18] A method for treating or preventing atopic dermatitis in a patient, comprising administering to a patient in need of a peptide described in any one of [1] to

[15] or [15-1], or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[19] Use of a peptide described in any one of [1] to

[15] or [15-1], or a pharmaceutically acceptable salt thereof, for the treatment or prevention of atopic dermatitis.

[20] Use of a peptide described in any one of [1] to

[15] or [15-1], or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical composition for the treatment or prevention of atopic dermatitis.

[21] A peptide described in any one of [1] to

[15] or [15-1], or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of atopic dermatitis.

[22] A peptide described in any one of [1] to

[15] or [15-1], or a pharmaceutically acceptable salt thereof, for use in the manufacture of a pharmaceutical composition for the treatment or prevention of atopic dermatitis. In addition, in [1] to

[22] , the peptide described in any one of [1] to

[15] or [15-1], or its pharmaceutically acceptable salt, may be a preferred embodiment described later.

[0013] According to the present invention, it is possible to provide a novel substance that targets the oncostatin M receptor (OSMR).

[0014] Expression changes of Osm and Osmr genes in a hereditary AD model. The vertical axis shows gene expression level (RPKM), and the horizontal axis shows age in weeks. Increased expression of Osm and Osmr genes in a drug-induced AD model. EtOH represents the control group, and MC903 represents the AD model. Comparison of Osm and Osmr gene expression levels in AD patients and healthy individuals. Changes in auricle thickness (mm) over time in each mouse to which the MC903-coated AD model was applied. Osm- / - represents Osm knockout mice, Osmr- / - represents Osmr knockout mice, and WT represents the control group. Gene expression analysis in WT mice and Osm knockout mice. Comparison of scratching behavior counts in WT mice. "saline" represents the group administered with physiological saline (negative control), "rOsm" represents the group administered with recombinant mouse Osm, and "BAM8-22" represents the group administered with BAM8-22 peptide (positive control). Comparison of the number of scratching behaviors in recombinant mouse Osm administration between mice lacking the Osmr gene and the control group. Evaluation of the OSM signaling activity inhibitory ability of OSMR7 by luciferase assay. The vertical axis represents luminescence intensity, the horizontal axis represents OSMR7 concentration (nM), and IC50 represents Half maximal inhibition concentration (μM). Suppression of SOCS3 gene expression by OSMR7. The vertical axis represents gene expression level, and the horizontal axis represents peptide concentration (nM). In the horizontal axis, "100%" represents the group stimulated with rhOSM without treatment with cyclic peptides, and "0%" represents the group that received neither treatment with cyclic peptides nor stimulation with rhOSM. Conceptual diagram of the mRNA library used for the preparation of OSMR7 analogs. From top to bottom, these are sequence numbers 23 to 39. Deep mutational scanning of OSMR7 analogs. Each number indicates the percentage of occurrence of the peptide with each amino acid residue substituted, with the occurrence rate of the original OSMR7 sequence set to 100% (sequence number 23). Evaluation of the OSM signaling inhibitory ability of each OSMR7 analog by luciferase assay. The vertical axis represents luminescence intensity, the horizontal axis represents cyclic peptide concentration (nM), and IC50 represents Half maximal inhibition concentration (μM). Suppression of SOCS3 gene expression by various OSMR7 analogs. The vertical axis shows gene expression level, and the horizontal axis shows peptide concentration (nM).In the horizontal axis, "100%" represents the group stimulated with rhOSM without treatment with cyclic peptides, and "0%" represents the group that received neither treatment with cyclic peptides nor stimulation with rhOSM. Evaluation of cytotoxicity upon administration of OSMR7 analogs. The vertical axis shows the survival rate (%) after 24 hours, and the horizontal axis shows the peptide concentration (μM). Suppressive effect of OSMR7_Mut7 on atopic dermatitis pruritus. (A) Induction of scratching behavior by subcutaneous administration of rhOSM. (B) Suppression of scratching behavior by subcutaneous administration of OSMR7_Mut7. Suppression of increase in auricle thickness by transdermal administration of OSMR7_Mut7. OSMR_Mut7 represents the peptide application group, and WT represents the control group.

[0015] The following describes in detail embodiments for carrying out the present invention (hereinafter referred to as "this embodiment"). It should be noted that the present invention is not limited to the following embodiments and can be implemented in various modifications within the scope of its gist.

[0016] [Peptides or pharmaceutically acceptable salts thereof] The peptides or pharmaceutically acceptable salts thereof according to this embodiment include a substructure having an amino acid sequence selected from the group consisting of (1) and (2) below.(1) An amino acid sequence represented by the following formula (I): RYRYYGHNLIAYGFY (I) (Sequence ID 1) (2) An amino acid sequence in which 1 to 6 amino acids are substituted in the amino acid sequence represented by the above formula (I), with arginine at the N-terminus being the first amino acid residue, the first amino acid residue may be substituted with a basic amino acid other than arginine and histidine, the second amino acid residue may be substituted with an aromatic amino acid other than tyrosine and histidine, the third amino acid residue may be substituted with a basic amino acid other than arginine and histidine, the fourth amino acid residue may be substituted with an aromatic amino acid other than tyrosine and histidine, the fifth amino acid residue may be substituted with an aromatic amino acid other than tyrosine or an amino acid containing a hydroxyl group, and the sixth amino acid residue may be substituted with alanine or its analogue, or a glycine analogue. The seventh amino acid residue may be substituted with an amino acid other than cysteine, lysine, proline, arginine, threonine, valine, and tryptophan; the eighth amino acid residue may be substituted with aspartic acid, glycine, tyrosine, phenylalanine, serine, histidine, glutamic acid, glutamine, alanine, leucine, or their analogues, or an asparagine analogue; the ninth amino acid residue may be substituted with an amino acid other than glycine, proline, and tryptophan; the tenth amino acid residue may be substituted with a branched-chain amino acid other than isoleucine; the eleventh amino acid residue may be substituted with an amino acid other than glycine, proline, and tryptophan; the twelfth amino acid residue may be substituted with a tyrosine analogue or a phenylalanine analogue; the thirteenth amino acid residue may be substituted with alanine, its analogue, or a glycine analogue. An amino acid sequence in which the 14th amino acid residue may be substituted with histidine, leucine, tyrosine, tryptophan, or analogs thereof, or an analog of phenylalanine, and the 15th amino acid residue may be substituted with an aromatic amino acid other than tyrosine and histidine.

[0017] Furthermore, the peptide according to this embodiment, or a pharmaceutically acceptable salt thereof, may include a substructure having an amino acid sequence having 80% identity with the amino acid sequence represented by formula (I) above. In this specification, the descriptions of formulas (1) and (2) also apply to formula (3). In addition, the substitution of formula (2) may be present within the range of identity in formula (3). In this specification, "having 80% or more identity" means that when the amino acid sequences of the two polypeptides are aligned to maximize the agreement, the ratio of the number of common amino acid residues to the total number of amino acids shown in formula (1) is 80% or more. The identity may be 85% or more, 90% or more, or 95% or more.

[0018] The peptide according to this embodiment, or its pharmaceutically acceptable salt, has a high binding affinity to the oncostatin M receptor (OSMR), as shown in the examples described below. Furthermore, the peptide according to this embodiment, or its pharmaceutically acceptable salt, can inhibit the transmission of the OSM signal, which is generated by the interaction of oncostatin M with the receptor OSMR. OSMR also complexes with the IL-31 receptor A (IL-31RA) to form an IL-31RA / OSMR complex. IL-31, an interleukin involved in the development of atopic dermatitis and pruritus, interacts with the IL-31RA / OSMR complex, thereby activating the IL-31 signaling pathway. Therefore, the peptide according to this embodiment, or its pharmaceutically acceptable salt, can inhibit the transmission of the IL-31 signal, which is generated by the interaction of IL-31 with the IL-31RA / OSMR complex involved in pruritus. Therefore, the peptides according to this embodiment, or pharmaceutically acceptable salts thereof, are useful for the treatment or prevention of diseases associated with OSM signaling, and in particular for the treatment or prevention of diseases associated with OSM signaling and / or pruritus-related IL-31 signaling, and are preferably useful for the treatment or prevention of atopic dermatitis.

[0019] In this specification, a pharmaceutically acceptable salt means a salt with a pharmaceutically acceptable base or acid. Examples of pharmaceutically acceptable salts are, but are not limited to, addition salts of inorganic acids (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), addition salts of organic acids (p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carboxylic acids, succinic acid, citric acid, benzoic acid, acetic acid, etc.), addition salts of inorganic bases (ammonium hydroxide or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, etc.), and addition salts of amino acids.

[0020] In this specification, amino acids include not only naturally occurring amino acids but also artificial amino acid variants and amino acid derivatives. While not particularly limited, examples of amino acids include natural amino acids, including proteinogenic amino acids, and unnatural amino acids.

[0021] When protein amino acids are represented by the three-letter abbreviations commonly used in this industry, they are Arg, His, Lys, Asp, Glu, Ser, Thr, Asn, Gln, Cys, Gly, Pro, Ala, Ile, Leu, Met, Phe, Trp, Tyr, and Val. Alternatively, when protein amino acids are represented by the single-letter abbreviations commonly used in this industry, they are R, H, K, D, E, S, T, N, Q, C, G, P, A, I, L, M, F, W, Y, and V. These 19 protein amino acids, excluding glycine, are L-amino acids; however, in this specification, amino acids also include D-amino acids corresponding to these 19 L-amino acids.

[0022] Furthermore, in this specification, amino acids include non-proteinogenic amino acids. Non-proteinogenic amino acids include natural amino acids other than proteinogenic amino acids, and unnatural amino acids. Unnatural amino acids are amino acids other than natural amino acids, and include, for example, chemically synthesized compounds that have properties known in the industry as characteristics of amino acids.

[0023] Non-proteinogenic amino acids are not particularly limited, but include, for example, amino acids whose main chain structure differs from that of proteinogenic amino acids (α,α-disubstituted amino acids (e.g., α-methylalanine, cycloleucine, etc.), N-alkyl amino acids (e.g., N-methyl amino acids, etc.), D-amino acids, β-amino acids, γ-amino acids, δ-amino acids, long-chain amino acids, α-hydroxy acids, α-thio acids, and cyclic amino acids (cyclic α-amino acids, cyclic β-amino acids, cyclic δ-amino acids, and aromatic amino acids, etc.)); amino acids whose side chain structure differs from that of proteinogenic amino acids (selenocysteine, norleucine, spinacine, nitrophenylalanine, tetrahydroisoquinoline carboxylic acid, tetrahydroisoquinoline carboxylic acid having substituents (e.g., hydroxyl groups, C1-C3 alkyl groups, halogen groups, etc.) (e.g., hydroxytetrahydroisoquinoline carboxylic acid, etc.), hydroxytryptophan, pentafluorophenylalanine, methoxyphenylalanine, γ Ｓ，Ｌ Examples include homoglutamine, amino acids having a structure consisting of multiple rings (e.g., bicycloamino acids), azide group-containing amino acids, alkyne group-containing amino acids, alkene group-containing amino acids, chloroacetamide group-containing amino acids, photoreactive group-containing amino acids, fluorescent amino acids, ε-alkylated lysine, biotin group-containing amino acids, citrulline, ester group-containing amino acids, amino acids having an additional methylene group in the side chain ("homo" amino acids; e.g., homophenylalanine, homoglutamine, and homohistidine), and amino acids in which the carboxylic acid functional group in the side chain is replaced with a sulfonic acid group (e.g., cysteic acid); and combinations thereof. Examples of these combinations include amino acids whose main chain structure and side chain structure differ from those of proteinaceous amino acids, N-methylated derivatives of the above amino acids in which the main chain amino group is methylated, and D amino acids of the above amino acids. Specific examples of other unnatural amino acids include those described in International Publication No. 2015 / 030014.

[0024] In this specification, an aromatic amino acid means an amino acid having an aromatic ring in its side chain. Aromatic amino acids are not particularly limited, but examples of protein amino acids include Trp, His, Phe, and Tyr. The aromatic ring of an aromatic amino acid may be a benzene ring, an indole ring, or an imidazole ring.

[0025] In this specification, a basic amino acid means an amino acid having a side chain that exhibits basicity. Basic amino acids are not particularly limited, but examples of protein amino acids include Arg, Lys, His, and Trp. Basic amino acids may have an amino group, a guanidino group, or an imidazole group in their side chains.

[0026] In this specification, an amino acid containing a hydroxyl group means an amino acid having a hydroxyl group. While there are no particular limitations on amino acids containing a hydroxyl group, examples of protein amino acids include Ser, Tyr, and Thr. In amino acids containing a hydroxyl group, the hydroxyl group may be contained within the side chain.

[0027] In this specification, branched-chain amino acids mean amino acids having a branched alkyl group in their side chains. Branched-chain amino acids are not particularly limited, but examples of protein amino acids include Val, Leu, and Ile. The number of carbon atoms in the branched alkyl group of a branched-chain amino acid may be 3 to 8, preferably 3 to 5.

[0028] The peptide or pharmaceutically acceptable salt according to this embodiment includes a substructure having an amino acid sequence selected from the group consisting of (1) to (3) or (1) and (2) above. The amino acid sequence of (2) above is an amino acid sequence in which 1 to 6 amino acids are substituted in the amino acid sequence represented by formula (I) above. In the amino acid sequence of (2) above, the number of amino acids substituted from the amino acid sequence represented by formula (I) is 1 to 6, preferably 1 to 5, more preferably 1 to 4, even more preferably 1 to 3, even more preferably 1 or 2, and particularly preferably 1.

[0029] In the amino acid sequence of (2) above, the amino acids to be substituted from the amino acid sequence represented by formula (I) can be selected as follows. In the following description of candidate amino acids to be substituted, the arginine at the N-terminus of the amino acid sequence represented by formula (I): RYRYYGHNLIAYGFY (Sequence ID 1) is considered the first amino acid residue. In the amino acid sequence of (3) above, the amino acids to be substituted from the amino acid sequence represented by formula (I) can be selected as follows.

[0030] The first amino acid residue, arginine, may be substituted with a basic amino acid other than arginine and histidine, lysine or its analogue, or an analogue of arginine, or lysine.

[0031] The second amino acid residue, tyrosine, may be substituted with an aromatic amino acid other than tyrosine and histidine, may be substituted with tryptophan, phenylalanine, or their analogues, or an analogue of tyrosine, may be substituted with tryptophan, or its analogue, an analogue of phenylalanine, or an analogue of tyrosine, may be substituted with an analogue of tyrosine or an analogue of phenylalanine, may be substituted with an analogue of tyrosine, or may be substituted with tryptophan.

[0032] The third amino acid residue, arginine, may be substituted with a basic amino acid other than arginine and histidine, lysine or its analog, or an analog of arginine, or an analog of arginine, or lysine.

[0033] The fourth amino acid residue, tyrosine, may be substituted with an aromatic amino acid other than tyrosine and histidine, may be substituted with tryptophan, phenylalanine, or their analogues, or an analogue of tyrosine, may be substituted with phenylalanine, its analogue, or an analogue of tyrosine, may be substituted with an analogue of tyrosine or phenylalanine, may be substituted with an analogue of tyrosine, or may be substituted with phenylalanine.

[0034] The fifth amino acid residue, tyrosine, may be substituted with an aromatic amino acid other than tyrosine or an amino acid containing a hydroxyl group, or with tryptophan, phenylalanine, histidine, serine, threonine, or their analogues, or an analogue of tyrosine, or with tryptophan, phenylalanine, serine, or their analogues, or an analogue of tyrosine, or with tryptophan, or its analogue, an analogue of phenylalanine, or an analogue of tyrosine, or with an analogue of tyrosine, or with an analogue of phenylalanine, or with an analogue of tyrosine, or with tryptophan, phenylalanine, histidine, serine, or threonine, or with tryptophan, phenylalanine, or serine.

[0035] The sixth amino acid residue, glycine, may be substituted with alanine, its analogue, or a glycine analogue.

[0036] The seventh amino acid residue, histidine, may be substituted with any amino acid other than cysteine, lysine, proline, arginine, threonine, valine, and tryptophan, and may be substituted with asparagine, aspartic acid, glycine, glutamine, serine, tyrosine, glutamic acid, isoleucine, alanine, leucine, phenylalanine, lysine, valine, threonine, arginine, tryptophan, or their analogues, or histidine analogues, and may be substituted with asparagine, aspartic acid, glycine, glutamine, serine, tyrosine, glutamic acid, isoleucine, alanine, leucine, phenylalanine, or their analogues, or histidine analogues, and may be substituted with asparagine, aspartic acid, glycine, glutamine, serine, tyrosine, glutamic acid, isoleucine, alanine, or their analogues It may be substituted with an analog or a histidine analog, asparagine, aspartic acid, glycine, glutamine, or their analogs, or a histidine analog, asparagine, aspartic acid, glycine, glutamine, serine, tyrosine, glutamic acid, isoleucine, alanine, leucine, phenylalanine, lysine, valine, threonine, arginine, or tryptophan, asparagine, aspartic acid, glycine, glutamine, serine, tyrosine, glutamic acid, isoleucine, alanine, leucine, or phenylalanine, asparagine, aspartic acid, glycine, glutamine, serine, tyrosine, glutamic acid, isoleucine, or alanine, or asparagine, aspartic acid, glycine, or glutamine.

[0037] The eighth amino acid residue, asparagine, may be substituted with glycine, aspartic acid, tyrosine, phenylalanine, serine, histidine, glutamic acid, glutamine, alanine, leucine, or their analogues, or an analogue of asparagine, and may be substituted with glycine, aspartic acid, tyrosine, phenylalanine, serine, histidine, or their analogues, or an analogue of asparagine, and may be substituted with glycine, aspartic acid, tyrosine, or their analogues, or an analogue of asparagine, and may be substituted with glycine, aspartic acid, or their analogues It may be substituted with log or an asparagine analog, glycine or an analog thereof, or an asparagine analog, glycine, aspartic acid, tyrosine, phenylalanine, serine, histidine, glutamic acid, glutamine, alanine, or leucine, glycine, aspartic acid, tyrosine, phenylalanine, serine, or histidine, glycine, aspartic acid, or tyrosine, glycine, aspartic acid, or tyrosine, glycine, or aspartic acid, or glycine.

[0038] The ninth amino acid residue, leucine, may be substituted with an amino acid other than glycine, proline, and tryptophan, such as glutamine, glutamic acid, valine, isoleucine, lysine, arginine, asparagine, histidine, serine, tyrosine, threonine, alanine, cysteine, phenylalanine, aspartic acid, or their analogues, or an analogue of leucine, and may be substituted with glutamine, glutamic acid, valine, isoleucine, lysine, arginine, asparagine, histidine, serine, tyrosine, threonine It may be substituted with soleucine, lysine, arginine, asparagine, histidine, or their analogues, or leucine analogues, and may be substituted with glutamine, glutamic acid, valine, isoleucine, lysine, arginine, asparagine, histidine, serine, tyrosine, threonine, alanine, cysteine, phenylalanine, or aspartic acid, and may be substituted with glutamine, glutamic acid, valine, isoleucine, lysine, arginine, asparagine, histidine, serine, tyrosine, or threonine, and may be substituted with glutamine, glutamic acid, valine, isoleucine, lysine, arginine, asparagine, or histidine.

[0039] The tenth amino acid residue, isoleucine, may be substituted with a branched-chain amino acid other than isoleucine, valine, leucine, or their analogues, or an analogue of isoleucine, or it may be substituted with valine.

[0040] The 11th amino acid residue, alanine, may be substituted with an amino acid other than glycine, proline, and tryptophan, such as threonine, serine, lysine, glutamine, leucine, asparagine, arginine, valine, histidine, aspartic acid, isoleucine, alanine, phenylalanine, glutamic acid, tyrosine, cysteine, or their analogues, or an analogue of alanine, such as threonine, serine, lysine, glutamine, leucine, asparagine, arginine. Nin, valine, histidine, aspartic acid, isoleucine, alanine, phenylalanine, glutamic acid, tyrosine, or their analogues, or alanine analogues may be substituted, and threonine, serine, lysine, glutamine, leucine, asparagine, arginine, valine, histidine, aspartic acid, isoleucine, alanine, phenylalanine, or their analogues, or alanine analogues may be substituted, and threonine, serine, lysine, glutamine, leucine It may be substituted with asparagine, arginine, valine, histidine, aspartic acid, isoleucine, or analogs thereof, or analogs of alanine, and may be substituted with threonine, serine, lysine, glutamine, leucine, asparagine, arginine, valine, histidine, aspartic acid, isoleucine, alanine, phenylalanine, glutamic acid, tyrosine, or cysteine, and may be substituted with threonine, serine, lysine, glutamine, leucine, asparagine, arginine, valine It may be substituted with histidine, aspartic acid, isoleucine, alanine, phenylalanine, glutamic acid, or tyrosine, and may be substituted with threonine, serine, lysine, glutamine, leucine, asparagine, arginine, valine, histidine, aspartic acid, isoleucine, alanine, or phenylalanine, and may be substituted with threonine, serine, lysine, glutamine, leucine, asparagine, arginine, valine, histidine, aspartic acid, or isoleucine.

[0041] The twelfth amino acid residue, tyrosine, may be substituted with a tyrosine analog or a phenylalanine analog, and may be substituted with a tyrosine analog.

[0042] The 13th amino acid residue, glycine, may be substituted with alanine, its analogue, or a glycine analogue.

[0043] The 14th amino acid residue, phenylalanine, may be substituted with histidine, leucine, tyrosine, tryptophan, or their analogues, or an analogue of phenylalanine; it may be substituted with histidine, leucine, tyrosine, or their analogues, or an analogue of phenylalanine; it may be substituted with tyrosine, or its analogue, or an analogue of phenylalanine; it may be substituted with histidine, leucine, tyrosine, or tryptophan; it may be substituted with histidine, leucine, or tyrosine; or it may be substituted with tyrosine.

[0044] The 15th amino acid residue, tyrosine, may be substituted with an aromatic amino acid other than tyrosine and histidine, may be substituted with tryptophan, phenylalanine, or their analogues, or an analogue of tyrosine, may be substituted with phenylalanine, or its analogue, or an analogue of tyrosine, may be substituted with an analogue of tyrosine or phenylalanine, may be substituted with an analogue of tyrosine, or may be substituted with phenylalanine.

[0045] Any of the above amino acid residues from position 1 to 15 may be substituted, and if there are multiple amino acid residues to be substituted, the combination is not particularly limited. In the amino acid sequences of (2) and (3) above, the nth amino acid (n is 1 to 15) to be substituted from the amino acid sequence represented by formula (I) can be independently selected from the above-mentioned candidates. If there are multiple amino acid residues to be substituted, adjacent amino acids may be substituted, and adjacent amino acids may be substituted via 1 to 13 amino acid residues (for example, 1 to 13, 2 to 12, 3 to 11, 4 to 10, 5 to 9, 6 to 8, 1 to 4, 1 to 3, etc.). The amino acids listed as candidates that can be substituted in the above amino acid residues from position 1 to 15 may be independently selected for each amino acid. For example, if we explain using the case where the first and second amino acid residues are substituted, the first amino acid residue, arginine, may be substituted with a basic amino acid other than arginine and histidine; lysine or its analog, or an analog of arginine; an analog of arginine; or lysine. The second amino acid residue, tyrosine, may be substituted independently of the amino acid substituted at the first amino acid residue, with a selection of aromatic amino acids other than tyrosine and histidine; tryptophan, phenylalanine, or their analogs, or an analog of tyrosine; tryptophan, or its analog, an analog of phenylalanine, or an analog of tyrosine; an analog of tyrosine or an analog of phenylalanine; an analog of tyrosine; or tryptophan.

[0046] In the amino acid sequence of (2) above, the amino acid to be substituted may be selected from the following. The nth amino acid (n is 1 to 15) below can be independently selected from the above candidates instead of the candidates below. The first amino acid residue may be substituted with an arginine analog, the second amino acid residue may be substituted with tryptophan or its analog, a phenylalanine analog, or a tyrosine analog, the third amino acid residue may be substituted with an arginine analog, the fourth amino acid residue may be substituted with phenylalanine or its analog, or a tyrosine analog, the fifth amino acid residue may be substituted with a tyrosine analog or a phenylalanine analog, the sixth amino acid residue may be substituted with a glycine analog, the seventh amino acid residue may be substituted with asparagine, aspartic acid, glycine, glutamine, serine, tyrosine, glutamic acid, isoleucine, alanine or their analogs, or a histidine analog, the eighth amino acid residue may be substituted with glycine or its analog, or an asparagine analog. The ninth amino acid residue may be substituted with glutamine, glutamic acid, valine, isoleucine, lysine, arginine, asparagine, histidine, or their analogues, or an analogue of leucine; the tenth amino acid residue may be substituted with valine, or its analogue, or an analogue of isoleucine; the eleventh amino acid residue may be substituted with threonine, serine, lysine, glutamine, leucine, asparagine, arginine, valine, histidine, aspartic acid, isoleucine, or their analogues, or an analogue of alanine; the thirteenth amino acid residue may be substituted with an analogue of glycine; the fourteenth amino acid residue may be substituted with tyrosine, or its analogue, or an analogue of phenylalanine; and the fifteenth amino acid residue may be substituted with an analogue of tyrosine or an analogue of phenylalanine. Here, the twelfth amino acid residue may be substituted with an analogue of tyrosine or an analogue of phenylalanine.

[0047] In this specification, analogs of proteinogenic amino acids (e.g., analogs of R, H, K, D, E, S, T, N, Q, C, G, P, A, I, L, M, F, W, Y, or V) include D-amino acids (excluding glycine), α,α-disubstituted amino acids (e.g., amino acids with a methyl group bonded at the α-position), N-alkyl amino acids (e.g., N-methyl amino acids), β-amino acids, γ-amino acids, δ-amino acids, α-hydroxy acids, amino acids having an additional methylene group in the side chain ("homo" amino acids; e.g., homophenylalanine, homoglutamine, and homohistidine), amino acids with an alkyl or aryl group bonded to the side chain, amino acids with a substituent bonded to an aromatic ring in the side chain, and combinations thereof.

[0048] In amino acids in which an alkyl group or aryl group is bonded to the side chain, the number of carbon atoms in the alkyl group is, for example, 1 to 10, preferably 1 to 5, more preferably 1 to 4, even more preferably 1 to 3, and particularly preferably 1. Examples of aryl groups include a phenyl group, a naphthyl group, and a benzyl group.

[0049] As examples of amino acids with an alkyl or aryl group attached to the side chain, we will explain using serine and cysteine ​​analogs as examples. An example of serine with an alkyl or aryl group attached to the side chain is represented by the following formula. [In the formula, R is an alkyl group or an aryl group. However, if R is a methyl group, it represents threonine.]

[0050] Examples of cysteines in which an alkyl group or aryl group is bonded to the side chain include those represented by the following formula. [In the formula, R is an alkyl group or an aryl group.]

[0051] The substituents in amino acids with substituents attached to the aromatic ring in the side chain are not particularly limited, but examples include: hydroxyl groups; amino groups; carboxyl groups; halogen groups such as fluorine, chloro, bromo, and iodo groups; C1-C10 alkyl groups such as methyl, ethyl, and propyl groups; aryl groups such as phenyl, naphthyl, and benzyl groups (including aralkyl groups); and aralkyloxy groups such as benzyloxy groups. Furthermore, amino acids with substituents attached to the aromatic ring in the side chain also include amino acids in which the functional group attached to the aromatic ring is substituted with the substituents mentioned above. For example, amino acids in which the hydroxyl group on the benzene ring in the side chain of tyrosine is replaced with an amino group; a carboxyl group; halogen groups such as fluorine, chloro, bromo, and iodo groups; C1-C10 alkyl groups such as methyl, ethyl, and propyl groups; aryl groups such as phenyl, naphthyl, and benzyl groups (including aralkyl groups); or aralkyloxy groups such as benzyloxy groups (especially amino groups) are analogs of tyrosine or phenylalanine. Examples of such amino acids include dibromotyrosine, pentafluorophenylalanine, bromophenylalanine, iodophenylalanine, chlorophenylalanine, nitrophenylalanine, and aminophenylalanine.

[0052] An analog of a proteinogenic amino acid (e.g., an analog of R, H, K, D, E, S, T, N, Q, C, G, P, A, I, L, M, F, W, Y, or V) is a D-amino acid (excluding glycine), an N-alkyl amino acid (e.g., N-methyl amino acid, etc.), or an amino acid having an additional methylene group in its side chain ("homo" amino acid; e.g., homo-methyl amino acid) of the proteinogenic amino acid (e.g., R, H, K, D, E, S, T, N, Q, C, G, P, A, I, L, M, F, W, Y, or V). Preferred amino acids include nyalanin, homoglutamine, and homohistidine, amino acids with a C1-C3 alkyl group or phenyl group attached to the side chain, amino acids with a substituent attached to the aromatic ring in the side chain, and combinations thereof. Preferably, the D-amino acids (excluding glycine) and N-alkyl amino acids (e.g., N-methyl amino acids) of the proteinaceous amino acids (e.g., R, H, K, D, E, S, T, N, Q, C, G, P, A, I, L, M, F, W, Y, or V) are preferred.

[0053] In the peptide according to this embodiment, or a pharmaceutically acceptable salt thereof, the substructure preferably includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21 shown in the following table, and more preferably an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21. The following amino acid sequences selected from the group consisting of SEQ ID NOs: 1 to 21 are more preferably OSMR7 (original), OSMR7_Mut6, OSMR7_Mut7, OSMR7_Mut15, and OSMR7_Mut18, with OSMR7_Mut7 being particularly preferred.

[0054]

[0055] The peptide according to this embodiment is preferably a cyclic peptide. In this case, it is preferable that a substructure having an amino acid sequence selected from the group consisting of (1) to (3) or (1) and (2) is included in the cyclic structure of the cyclic peptide. In this case, it is sufficient if a part of the substructure is included in the cyclic structure of the cyclic peptide, but it is preferable that the entire substructure, that is, all of the amino acids forming the substructure, are included in the cyclic structure of the cyclic peptide.

[0056] In this specification, "peptide" means a compound formed by the linkage of multiple amino acids. Furthermore, "cyclic peptide" means a peptide that has at least a cyclic structure formed by multiple amino acids within its molecule. The molecular structure of a cyclic peptide may also have a chain-like structure in which amino acids are linked by peptide bonds, or it may have a structure other than a peptide structure.

[0057] In this specification, a cyclic structure means a closed-ring structure formed within a linear peptide molecule by the direct or mediated linking of two amino acids separated by one or more amino acid residues. "Separated by one or more amino acid residues" means that there is at least one amino acid residue between the two amino acids forming the closed-ring structure.

[0058] The ring-closing structure in a cyclic structure is not particularly limited, but is formed by the covalent bonding of two amino acids via a linker or the like, as needed. While not particularly limited, examples of covalent bonds between two amino acids include disulfide bonds, peptide bonds, alkyl bonds, alkenyl bonds, ester bonds, thioester bonds, ether bonds, thioether bonds, phosphonate ether bonds, azo bonds, and N-CO-CH ２ Examples of covalent bonds include S-bonds, C-S-C bonds, C-N-C bonds, C=N-C bonds, amide bonds, lactam crosslinks, carbamoyl bonds, urea bonds, thiourea bonds, amine bonds, and thioamide bonds. When two amino acids are bonded in the main chain of an amino acid, a ring-closing structure is typically formed by a peptide bond. In addition, covalent bonds between two amino acids may be formed by the bonding of the side chains of the two amino acids, or by the bonding of the side chains of the two amino acids to the main chain, etc.

[0059] The cyclic structure is not limited to a structure formed by the bonding of the N-terminus and C-terminus amino acids of a linear peptide, but may also be formed by the bonding of a terminal amino acid to a non-terminal amino acid, or by the bonding of non-terminal amino acids to each other. The terminal amino acid may be either the N-terminus or the C-terminus. When one of the amino acids bonded to form the cyclic structure is a terminal amino acid and the other is a non-terminal amino acid, the cyclic peptide has a structure in which a linear peptide is attached to the cyclic structure like a tail. When the cyclic structure has a structure in which a linear peptide is attached to the cyclic structure like a tail, it is preferable that the linear peptide is bonded to the C-terminus amino acid that forms the cyclic structure in the linear peptide.

[0060] The cyclic structure in a cyclic peptide can be obtained, for example, by forming a closed ring structure between an amino acid having functional group 1 and an amino acid having the corresponding functional group 2, as shown in the table below. Either functional group 1 or functional group 2 may be at the N-terminus. Functional groups 1 and 2 may be positioned at the N-terminus and C-terminus, one may be a terminal amino acid (either N-terminus or C-terminus) and the other a non-terminal amino acid, or both may be non-terminal amino acids. The bond formed by functional group 1 and functional group 2 can be considered a chemical cross-linking structure for forming the molecular cyclic structure in a cyclic peptide.

[0061]

[0062] In the chemical structural formulas in the table above, X １ is a leaving group, and Ar is an aromatic ring which may have substituents. Examples of leaving groups include halogen atoms such as Cl, Br, and I.

[0063] As an amino acid having the functional group (A-1), for example, chloroacetylated amino acids can be used. Examples of chloroacetylated amino acids include N-chloroacetyl-L-alanine, N-chloroacetyl-L-phenylalanine, N-chloroacetyl-L-tyrosine, N-chloroacetyl-L-tryptophan, N-3-(2-chloroacetamido)benzoyl-L-phenylalanine, N-3-(2-chloroacetamido)benzoyl-L-tyrosine, N-3-(2-chloroacetamido)benzoyl-L-tryptophan, β-N-chloroacetyl-L-diaminopropanoic acid, γ-N-chloroacetyl-L-diaminobutyric acid, δ-N-chloroacetyl-L-ornithine, ε-N-chloroacetyl-L-lysine, and corresponding D-amino acid derivatives. As amino acids having the functional group (A-1), N-chloroacetyl-L-tyrosine and N-chloroacetyl-D-tyrosine are preferably used.

[0064] Examples of amino acids having the functional group (A-2) include cysteine, homocysteine, mercaptonorvaline, mercaptonorleucine, 2-amino-7-mercaptoheptanoic acid, and 2-amino-8-mercaptooctanoic acid. Among the amino acids having the functional group (A-2), cysteine ​​is preferably used.

[0065] Examples of cyclization methods using an amino acid having the functional group (A-1) and an amino acid having the functional group (A-2) include those described in Kawakami, T. et al., Nature Chemical Biology 5, 888-890 (2009); Yamagishi, Y. et al., ChemBioChem 10, 1469-1472 (2009); Sako, Y. et al., Journal of American Chemical Society 130, 7932-7934 (2008); Goto, Y. et al., ACS Chemical Biology 3, 120-129 (2008); Kawakami T. et al, Chemistry & Biology 15, 32-42 (2008), and International Publication No. 2008 / 117833, among others.

[0066] Examples of amino acids having the functional group (B-1) include propargylglycine, homopropargylglycine, 2-amino-6-heptynoic acid, 2-amino-7-octynoic acid, and 2-amino-8-nonynoic acid. 4-pentynoylated or 5-hexynoylated amino acids may also be used. Examples of 4-pentynoylated amino acids include N-(4-pentenoyl)-L-alanine, N-(4-pentenoyl)-L-phenylalanine, N-(4-pentenoyl)-L-tyrosine, N-(4-pentenoyl)-L-tryptophan, N-3-(4-pentynoylamido)benzoyl-L-phenylalanine, N-3-(4-pentynoylamido)benzoyl-L-tyrosine, N-3-(4-pentynoylamido)benzoyl-L-tryptophan, β-N-(4-pentenoyl)-L-diaminopropanoic acid, γ-N-(4-pentenoyl)-L-diaminobutyric acid, σ-N-(4-pentenoyl)-L-ornithine, ε-N-(4-pentenoyl)-L-lysine, and their corresponding D-amino acid derivatives. Examples of 5-hexynoylated amino acids include those in which the 4-pentynoyl group is replaced with a 5-hexynoyl group, as exemplified by the compounds used as 4-pentynoylated amino acids.

[0067] Examples of amino acids having the functional group (B-2) include azidoalanine, 2-amino-4-azidobutanoic acid, azidoptonorvaline, azidonorleucine, 2-amino-7-azidoheptanoic acid, and 2-amino-8-azidooctanoic acid. Amino acids that have been azidoacetylated or 3-azidopentanoylated can also be used. Examples of azidoacetylated amino acids include N-azidoacetyl-L-alanine, N-azidoacetyl-L-phenylalanine, N-azidoacetyl-L-tyrosine, N-azidoacetyl-L-tryptophan, N-3-(4-pentynoylamido)benzoyl-L-phenylalanine, N-3-(4-pentynoylamido)benzoyl-L-tyrosine, N-3-(4-pentynoylamido)benzoyl-L-tryptophan, β-N-azidoacetyl-L-diaminopropanoic acid, γ-N-azidoacetyl-L-diaminobutyric acid, σ-N-azidoacetyl-L-ornithine, ε-N-azidoacetyl-L-lysine, and their corresponding D-amino acid derivatives. Examples of 3-azidopentanoylated amino acids include those compounds exemplified as azidoacetylated amino acids, in which the azidoacetyl group is replaced with a 3-azidopentanoyl group.

[0068] A cyclization method using an amino acid having the functional group (B-1) and an amino acid having the functional group (B-2) is described, for example, in Sako, Y. et al., Journal of American Chemical Society 130, 7932-7934 (2008), and International Publication No. 2008 / 117833, etc.

[0069] Examples of amino acids having the (C-1) functional group include N-(4-aminomethyl-benzoyl)-phenylalanine (AMBF) and 3-aminomethyltyrosine. Examples of amino acids having the (C-2) functional group include 5-hydroxytryptophan (WOH). Examples of cyclization methods using an amino acid having the (C-1) functional group and an amino acid having the (C-2) functional group include the method described in Yamagishi, Y. et al., ChemBioChem 10, 1469-1472 (2009) and International Publication No. 2008 / 117833.

[0070] Examples of amino acids having the (D-1) functional group include 2-amino-6-chloro-hexynoic acid, 2-amino-7-chloro-heptynoic acid, and 2-amino-8-chloro-octynoic acid. Examples of amino acids having the (D-2) functional group include cysteine, homocysteine, mercaptonorvaline, mercaptonorleucine, 2-amino-7-mercaptoheptanoic acid, and 2-amino-8-mercaptooctanoic acid. A method for cyclization using an amino acid having the (D-1) functional group and an amino acid having the (D-2) functional group is, for example, the method described in International Publication No. 2012 / 074129.

[0071] Examples of amino acids in (E-1) include N-3-chloromethylbenzoyl-L-phenylalanine, N-3-chloromethylbenzoyl-L-tyrosine, N-3-chloromethylbenzoyl-L-tryptophan, and their corresponding D-amino acid derivatives. Examples of amino acids in (E-2) include cysteine, homocysteine, mercaptonorvaline, mercaptonorleucine, 2-amino-7-mercaptoheptanoic acid, and 2-amino-8-mercaptooctanoic acid. Cyclization methods using amino acids having the functional groups of (E-1) and (E-2) can be carried out by referring to, for example, the cyclization methods of (A-1) and (A-2) or (D-1) and (D-2).

[0072] In this embodiment, the peptide is preferably cyclized by a cyclization reaction between the functional groups (A-1) and (A-2). In this case, the peptide is CO-CH ２ - It has an S structure. The amino acid having the functional group (A-1) is preferably located on the N-terminal side of the above substructure, and the amino acid having the functional group (A-2) is preferably located on the C-terminal side of the amino acid having (A-1). The amino acid having the functional group (A-1) is preferably an aromatic amino acid, more preferably an amino acid in which the functional group (A-1) is bonded to tryptophan, phenylalanine, tyrosine, or histidine, or an analog thereof, and more preferably an amino acid in which the functional group (A-1) is bonded to tryptophan or an analog thereof. The amino acid having the functional group (A-1) is preferably located at the N-terminus, in which case the functional group (A-1) is preferably a chloroacetyl group bonded to an amino group. In this case, the peptide cyclized by the cyclization reaction between the functional group (A-1) and the functional group (A-2) is N-CO-CH ２ -S structure, for example NH-CO-CH ２- It has an S structure. The amino acid having the functional group (A-2) is preferably an amino acid containing a sulfhydryl group in its side chain, and more preferably cysteine ​​or an analog thereof. The amino acid having the functional group (A-2) is preferably located closer to the C-terminus than the amino acid having the functional group (A-1), but may be included as one of the amino acids forming the above substructure, may be located on the C-terminus side of the above substructure, or may be located at the C-terminus. The amino acid having the functional group (A-2) is preferably located on the C-terminus side of the above substructure.

[0073] The peptide according to this embodiment preferably contains an aromatic amino acid at the N-terminus of the above-mentioned partial structure, and an amino acid having a sulfhydryl group at the C-terminus of the aromatic amino acid, wherein the aromatic amino acid and the amino acid having the sulfhydryl group are bonded to form a cyclic structure. The aromatic amino acid preferably has a functional group (A-1), and the aromatic amino acid having the functional group (A-1) and the amino acid having the sulfhydryl group form an N-CO-CH ２ - It is preferable to form an S structure.

[0074] The peptide according to this embodiment is preferably represented by the following formula (II).

[0075] In the above formula (II), S represents the thiol group of cysteine. In this specification and the figures attached thereto, the above structure is represented as -CH ２ The structure represented by -CO- is also written as Ac. Also, X １ The carbonyl group that is attached is the amino acid X １It is bonded to the main chain amino group. Furthermore, in formula (II) above, the portion represented as "partial structure" represents a partial structure having an amino acid sequence selected from the group consisting of (1) to (3) or (1) and (2). In formula (II) above, as the partial structure, the embodiments described as preferred, more preferred, even more preferred embodiments, etc. (hereinafter referred to as "preferred embodiments, etc.") are preferred. More specifically, for example, an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to SEQ ID NOs: 21 or an amino acid sequence containing any of them is preferred. In formula (II) above, X １ , and Xaa are each an amino acid, and X ２ OH, NH ２ , or (Xaa') ｒ (Xaa' is the aforementioned X １ X is an amino acid independently of Xaa, where n and m are integers from 0 to 5, and r is an integer from 1 to 20. In formula (II), X ２ (Xaa') ｒ If so, (Xaa') ｒ And, X ２ The bond to the carbonyl group to which it is attached may be a covalent bond at a group capable of binding to a carbonyl group present in the amino acid, and may be a covalent bond such as an amide bond, ester bond, thioester bond, or imide bond, or it may be an acid anhydride structure. Examples of groups capable of binding to a carbonyl group present in the amino acid include (Xaa'). ｒ It may also be the amino group at the N-terminus Xaa', (Xaa') ｒ (Xaa') at any position within the side chain amino group, side chain hydroxyl group, etc. ｒ It may be a group that can bind to a carbonyl group present in the amino acid side chain as any Xaa'. For any group that can bind to a carbonyl group present in the amino acid side chain as any Xaa', X ２A group present in the amino acid to which the carbonyl group to which is bonded is selected, and the covalent bond with the group present in the amino acid may be a covalent bond mediated by a nitrogen atom, oxygen atom, sulfur atom, etc. Taking histidine, tryptophan, and tyrosine as examples, the covalent bond may be a bond mediated by a nitrogen atom or oxygen atom present in these amino acids. In formula (II), X ２ (Xaa') ｒ In that case, preferably (Xaa'). ｒ The N-terminus of is bonded to the carbonyl group of formula (II).

[0076] In formula (II), X １ This is an amino acid in which an acetyl group is bonded to the N-terminal amino group, and the amino acid is preferably an aromatic amino acid, more preferably tryptophan, phenylalanine, tyrosine, or histidine, or an analog thereof, even more preferably tryptophan or an analog thereof, and particularly preferably tryptophan.

[0077] In formula (II), n and m are each independently preferably 0 to 3, more preferably 0 to 2, even more preferably 0 to 1, and even more preferably 0.

[0078] In formula (II), Xaa' is preferably glycine or serine, more preferably glycine. If there are multiple Xaa', each of the multiple Xaa' may be independently selected from glycine or serine, and all of the multiple Xaa' may be glycine. r is preferably 1 to 10, more preferably 1 to 8, even more preferably 1 to 5, and even more preferably 1 to 3. Within this range, r may be 1 or more, 2 or more, 3 or more, or 4 or more. (Xaa') ｒ For example, (-Gly-Ser) ｒ１ Structures represented by (r1 represents an integer from 1 to 10) or (-Gly-) ｒ (r is synonymous with the above.) A structure represented by this is given: (Xaa') ｒ If serine is included, X ２The bond between the carbonyl group and the serine may be formed via the hydroxyl group of the serine side chain.

[0079] In formula (II), X ２ Preferably, OH, NH ２ , or (Xaa') ｒ (r may be within the range described above as preferred embodiments, etc., and Xaa' may be within the range described above as preferred embodiments, etc., (Xaa') ｒ This may be one of the preferred embodiments described above, and more preferably (Xaa') ｒ (r may be within the range described above as preferred embodiments, etc., and Xaa' may be within the range described above as preferred embodiments, etc., (Xaa') ｒ This may be any of the preferred embodiments described above.) In formula (II), X ２ (Xaa') ｒ If so, (Xaa') ｒ The amino group at the N-terminus Xaa' is X ２ It is preferable that the carbonyl group bonded to it is bonded to it.

[0080] The peptide according to this embodiment is preferably represented by the following formula (III).

[0081] In the above formula (III), S is the part represented as "partial structure", X ２ ,r, and Xaa' are synonymous with formula (II), and preferred embodiments are the same as those of formula (II). For example, the portion represented as "partial structure" is preferably an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21, or an amino acid sequence containing any of them. The carbonyl group bound to the N-terminal tryptophan is bound to the amino group of the tryptophan main chain. In formula (III), X ２ (Xaa') ｒ If so, (Xaa') ｒ The amino group at the N-terminus Xaa' is X ２ It is preferable that the carbonyl group bonded to it is bonded to it.

[0082] The number of amino acid residues forming the peptide according to this embodiment is not particularly limited as long as it is 15 or more, but is preferably 15 to 50, more preferably 15 to 30, even more preferably 16 to 25, and even more preferably 17 to 20. Within the above range, the number of amino acid residues forming the peptide may be 18 or more, 40 or less, 35 or less, 22 or less, 19 or less, or 18 or less.

[0083] In the peptide according to this embodiment, the number of amino acid residues forming a cyclic structure is, for example, 15 to 50, more preferably 15 to 30, even more preferably 16 to 25, and even more preferably 17 to 20. Within the above range, the number of amino acid residues forming a cyclic structure may be 18 or more, 40 or less, 35 or less, 22 or less, 19 or less, or 18 or less.

[0084] The peptide according to this embodiment preferably includes one of the following structures. In the following structures, n means D-Asn and d means D-Asp. Also, X ２ OH, NH ２ , or (Xaa') ｒ Xaa' is an amino acid, and r is an integer between 1 and 20. ２ (Xaa') ｒ If so, (Xaa') ｒ The amino group at the N-terminus Xaa' is X ２ It is preferable that it is bonded to the carbonyl group that is bonded to X. ２ , Xaa', r, and (Xaa') ｒ The preferred embodiments are the same as those of formula (II). In the following structure, an acetyl group is bonded to the amino group of the main chain of tryptophan at the N-terminus, NH-CO-CH ２ This means that it has a ring-closing structure due to -S. The amino acid sequence in the structure shown in the top panel is SEQ ID NO: 44, the amino acid sequences in the structure shown in the middle panel are SEQ ID NOs: 45 and 46 from left to right, and the amino acid sequences in the structure shown in the bottom panel are SEQ ID NOs: 47 and 48 from left to right.

[0085] The peptide according to this embodiment preferably comprises one of the following structures, and more preferably one of the following structures. In the following structures, n represents D-Asn and d represents D-Asp. In the following structure, an acetyl group is bonded to the amino group of the main chain of tryptophan at the N terminus, resulting in NH-CO-CH ２ This means that it has a ring-closing structure due to -S. The amino acid sequence in the structure shown in the top panel is SEQ ID NO: 22, the amino acid sequences in the structure shown in the middle panel are SEQ ID NOs: 40 and 41 from left to right, and the amino acid sequences in the structure shown in the bottom panel are SEQ ID NOs: 42 and 43 from left to right.

[0086] [Method for Producing Peptides] The peptides according to this embodiment may be produced by solid-phase or liquid-phase chemical synthesis, or by a method using a translation synthesis system. Methods using a translation synthesis system include methods using a cell-free translation system and methods using a cell translation system. When producing the peptides according to this embodiment using a cell-free translation system, the peptide may be prepared by preparing a nucleic acid encoding the peptide and translating the nucleic acid in the cell-free translation system. The nucleic acid encoding the peptide can be appropriately designed by a person skilled in the art using the genetic code used in the translation system of a living organism, a reprogrammed genetic code, or a combination thereof. The nucleic acid may be DNA or RNA.

[0087] Using a cell-free translation system, it is possible to efficiently introduce non-natural amino acids into peptides, in addition to natural amino acids, by using tRNA aminoacylated with non-natural amino acids. For example, using the artificial aminoacyl-tRNA synthetase flexizyme, it is possible to aminoacylate tRNA with any anticodon using any natural or non-natural amino acid. Therefore, using this technology, the genetic code consisting of mRNA triplets can be reprogrammed to encode amino acids different from those in the biological translation system (International Publication No. 2008 / 059823).

[0088] [Pharmaceutical Composition] The pharmaceutical composition according to this embodiment comprises the peptide according to this embodiment, or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to this embodiment may be used for the treatment or prevention of disease. The pharmaceutical composition may use the peptide according to this embodiment, or a pharmaceutically acceptable salt thereof, as an active ingredient, or it may be formulated by adding a pharmaceutically acceptable carrier and / or additive. The proportion of the carrier or additive may be set appropriately based on the range commonly used in the pharmaceutical field.

[0089] The carriers and additives are not particularly limited, but examples include water, physiological saline, other aqueous solvents, and aqueous or oily bases, as well as alcoholic solvents, oily solvents, organic solvents, excipients, binders, pH adjusters, penetration enhancers, stabilizers, adhesives, disintegrants, lubricants, solvents, solubilizers, colorants, flavoring and deodorizing agents, stabilizers, emulsifiers, absorption enhancers, surfactants, preservatives, wetting agents, dispersants, antioxidants, and fragrances.

[0090] The form in which the pharmaceutical composition is formulated is not particularly limited, but examples include oral preparations such as tablets, powders, granules, and capsules, or parenteral preparations such as ointments, creams, lotions, sprays, tapes, injections, infusions, suppositories, and patches. The pharmaceutical composition according to this embodiment is not particularly limited, but it is preferably formulated as a parenteral preparation.

[0091] The carriers and additives used in formulation are not particularly limited, but examples include purified water, saline solution, phosphate buffer, pharmaceutically acceptable organic solvents such as dextrose, glycerol, and ethanol, animal and vegetable oils, lactose, mannitol, glucose, sorbitol, crystalline cellulose, hydroxypropyl cellulose, starch, corn starch, anhydrous silicic acid, aluminum magnesium silicate, collagen, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium carboxymethylcellulose, sodium polyacrylate, sodium alginate, water-soluble dextran, sodium carboxymethyl starch, pectin, methylcellulose, ethylcellulose, xanthan gum, acacia gum, tragacanth, casein, agar, polyethylene glycol, diglycerin, glycerin, propylene glycol, petrolatum, paraffin, octyldodecyl myristate, isopropyl myristate, higher alcohols, stearyl alcohol, stearic acid, and human serum albumin.

[0092] The dosage and administration interval of the active ingredient in the pharmaceutical composition may be appropriately selected depending on the target recipient, route of administration, disease, age, weight, and symptoms. Typically, when administered as a topical skin preparation, for example, 10 ng to 5000 mg or 10 μg to 500 mg per day may be administered. Alternatively, a sufficient amount may be administered based on the recommended daily dose (FTU). The administration interval may be once a day with the desired dosage, or divided into several doses.

[0093] The dosage of the active ingredient in the pharmaceutical composition may be calculated based on the Human Equivalent Dose (HED). For example, if the peptide according to this embodiment is effective in mice, the dose that produces an equivalent effect in humans may be calculated by dividing the mouse dose by 12.3, assuming a mouse body weight of 30 g and a human body weight of 60 kg. Alternatively, it may be determined based on an animal-to-human conversion model, such as that described in Journal of Basic and Clinical Pharmacy, 7(2), 27-31.

[0094] The target to which the pharmaceutical composition according to this embodiment is administered is not particularly limited, but is, for example, a mammal. Examples of mammals, not particularly limited, include humans, non-human primates, domesticated animals (including pets, service animals, and farm animals such as racehorses), laboratory animals, and livestock, with humans being preferred.

[0095] The pharmaceutical composition according to this embodiment may be administered in combination with one or more other agents. In combination administration, the pharmaceutical composition according to this embodiment may be administered simultaneously with or separately from the other agents. When administered simultaneously, the two or more active ingredients may be in the same formulation or administered as separate formulations. When administered separately, the two or more active ingredients may be administered according to a desired administration regimen. The dosage and administration interval of the other active ingredients may be in accordance with a predetermined administration regimen.

[0096] This embodiment also includes the following embodiments: a method for treating or preventing a disease in a patient, comprising administering an effective amount of the peptide according to this embodiment, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to this embodiment, to a patient in need; the use of the peptide according to this embodiment, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of a disease; the use of the peptide according to this embodiment, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical composition for the treatment or prevention of a disease; the peptide according to this embodiment, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease; the peptide according to this embodiment, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a pharmaceutical composition for the treatment or prevention of a disease. Here, it is preferable to use the peptide according to this embodiment, or a pharmaceutically acceptable salt thereof, as described above in preferred embodiments, etc.

[0097] This embodiment also includes the following aspects: a method for treating or preventing atopic dermatitis in a patient, comprising administering an effective amount of a peptide containing an amino acid sequence selected from SEQ ID NOs: 1 to 21 as a substructure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, to a patient in need; the use of a peptide containing an amino acid sequence selected from SEQ ID NOs: 1 to 21 as a substructure, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of atopic dermatitis; the use of a peptide containing an amino acid sequence selected from SEQ ID NOs: 1 to 21 as a substructure, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical composition for the treatment or prevention of atopic dermatitis; a peptide containing an amino acid sequence selected from SEQ ID NOs: 1 to 21 as a substructure, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of atopic dermatitis; a peptide containing an amino acid sequence selected from SEQ ID NOs: 1 to 21 as a substructure, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a pharmaceutical composition for the treatment or prevention of atopic dermatitis.

[0098] This embodiment also includes the following aspects: a method for treating or preventing atopic dermatitis in a patient, comprising administering an effective amount of a peptide containing an amino acid sequence selected from SEQ ID NOs: 44 to 48, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, to a patient in need; the use of a peptide containing an amino acid sequence selected from SEQ ID NOs: 44 to 48, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of atopic dermatitis; the use of a peptide containing an amino acid sequence selected from SEQ ID NOs: 44 to 48, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical composition for the treatment or prevention of atopic dermatitis; a peptide containing an amino acid sequence selected from SEQ ID NOs: 44 to 48, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of atopic dermatitis; a peptide containing an amino acid sequence selected from SEQ ID NOs: 44 to 48, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of atopic dermatitis.

[0099] In this specification, treatment or prevention means therapeutic and / or prophylactic measures. Therapeutic or prophylactic measures are approved in the Art and may include administration to a subject of a pharmaceutical composition. A therapeutic measure may mean administration after the onset of findings of an undesirable condition (e.g., the disease of the subject or other undesirable condition) and may be intended to reduce, suppress, restore, alleviate or stabilize an existing undesirable condition or its side effects. It may also include attenuation of any direct or indirect pathological effects of the disease, and prevention of infection. It may also mean measures to delay the onset of the disease or slow the progression of the disease. A prophylactic measure may mean administration before the onset of clinical findings of an undesirable condition and may be intended to suppress and / or prevent the recurrence of the undesirable condition.

[0100] The above diseases may be diseases related to OSM signaling, and may be diseases that can be treated or prevented by inhibiting OSM signaling, for example, diseases accompanied by itching, specifically dermatitis, atopic dermatitis, etc. The above diseases may be diseases that can be treated or prevented by inhibiting the interaction between oncostatin M (OSM) and the oncostatin M receptor (OSMR). Furthermore, the above diseases may be diseases related to OSM signaling and / or IL-31 signaling, and may be diseases that can be treated or prevented by inhibiting OSM signaling and / or IL-31 signaling, for example, diseases accompanied by itching, specifically dermatitis, atopic dermatitis, etc. The above diseases may be diseases that can be treated or prevented by inhibiting the interaction between oncostatin M (OSM) and / or IL-31 and the oncostatin M receptor (OSMR).

[0101] Oncostatin M (OSM) is a cytokine belonging to the interleukin-6 (IL-6) group and is expressed in macrophages and other immune cells. OSM is a type of inflammatory cytokine and may be involved in inflammation, hematopoiesis, and nervous system development. OSM signaling refers to the signal transduction pathway activated by OSM, a type of cytokine. OSM binds to the OSM receptor (OSMR) and may be involved in the development of atopic dermatitis by activating downstream signaling pathways such as JAK-STAT and MAPK.

[0102] In this specification, atopic dermatitis (AD) includes diseases characterized primarily by itchy eczema that repeatedly worsens and improves. "Itching" refers to an unpleasant skin sensation that triggers an urge to scratch.

[0103] Symptoms of atopic dermatitis include, for example, skin rashes, dermatitis, redness, desquamation, eczema, erythema, papules, nodules, lichenification, infiltration (oozing), crusting (scabs), itching, and erosions, as described in the "Atopic Dermatitis Treatment Guidelines 2024" (Journal of the Japanese Dermatological Association, 134(11), 2741-2843, 2024) created by the Japanese Dermatological Association.

[0104] Atopic dermatitis can occur on any part of the body. The location is not particularly limited, but examples include the face (cheeks, chin, forehead, around the eyes, around the mouth / lips, around the auricle), intertriginous areas (neck, armpits, elbow fossa, popliteal fossa), chest and abdomen, back, limbs, joints, trunk, etc.

[0105] Specific examples of atopic dermatitis include, but are not limited to, contact dermatitis, rashes, eczema, erythroderma, xerotic dermatitis, papules, nodules, insect bites, seborrheic dermatitis, prurigo simplex, scabies, miliaria, heat rash, ichthyosis, ichthyosis vulgaris, xerotic eczema, hand eczema, chapped hands, cutaneous lymphoma, mycosis fungoides, Sezary syndrome, psoriasis, Wiskott-Aldrich syndrome, impetigo, herpes simplex, and candidiasis. Examples include atopic dermatitis, hyper-IgE syndrome, skin abscess, cold abscess, systemic lupus erythematosus, discoid rash, mature scar, hypertrophic scar, keloid, scar contracture, dermatomyositis, edematous purplish-red macules (heliotrope rash), keratotic erythema (Gottron's sign), Netherton syndrome, and other diseases described in the "Atopic Dermatitis Treatment Guidelines 2024" (Japanese Journal of Dermatology, 134(11), 2741-2843, 2024).

[0106] In this embodiment, for example, administration of the pharmaceutical composition of this embodiment can suppress itching, suppress inflammation such as eczema, improve the condition of the skin, or improve various symptoms caused by atopic dermatitis. In particular, itching is suppressed.

[0107] In any of the embodiments described herein, any combination of the embodiments described herein and the embodiments described herein as preferred embodiments, etc., may be used.

[0108] [1. The relationship between the pathogenesis of atopic dermatitis (AD) and OSM / OSMR] (1.1 Creation of AD model mice) As a hereditary AD model, a Jak1 mouse with an overactive point mutation in the Jak1 gene locus was created. Ｓｐａｄｅ The model (Yasuda T. et al., J Clin Invest. 2016) was used. In addition, vitamin D was used as a drug-induced AD model. ３ A model was used in which the analog MC903 was applied to the auricle every 12 days (Li M. et al., PNAS. 2006, Oetjen LK et al. Cell. 2017) (hereinafter also referred to as the "MC903 AD model").

[0109] (1.2 Upregulation of Osm and Osmr gene expression in AD models) 1.2.1 Test using a hereditary AD model Jak1 Ｓｐａｄｅ The model is one in which atopic dermatitis-like symptoms develop in the auricle after 8 weeks of age (Yasuda T. et al., J Clin Invest. 2016). Jak1 Ｓｐａｄｅ Ear tissue samples were collected at different time points from mice and a control group of wild-type mice (WT; C57BL6 / J), and the expression changes of the Osm and Osmr genes were analyzed by RNA sequencing (RNA-seq). Specifically, RNA was extracted and purified from the collected ear tissue using TRIZOL reagent (Invitrogen), and a sequencing library was prepared using the TruSeq RNA Library Prep Kit (Illumina). The gene sequences were determined using the HiSeq 2500 sequencing system (Illumina). Ear tissue samples were collected at 1, 2, 4, 1, 2, 3, 4, 5, 6, 7, 8, 10, and 12 weeks after birth. The expression changes of the Osm and Osmr genes are shown in Figure 1. Jak1 Ｓｐａｄｅ In mice, it was confirmed that the expression levels of the Osm and Osmr genes increased in conjunction with the onset of dermatitis after 8 weeks of age.

[0110] 1.2.2 Drug-Induced AD Models The expression levels of the Osm and Osmr genes in drug-induced AD models were analyzed. Ear tissue was collected from MC903 AD models and control groups (ethanol-coated mice) at 8 weeks of age. Tissue RNA was then purified using TRIZOL reagent, Maxwell® 16LEV simplyRNA Purification Kits (Promega), and Maxwell 16 system instrument (Promega). Complementary DNA (cDNA) was synthesized from the RNA using PrimeScript II RT reagent Kit (TaKaRa). Synthesized cDNA was amplified using quantitative polymerase chain reaction (qPCR) with TB Green Premix Ex Taq reagent (TaKaRa) and a LightCycle 480 System II instrument (Roche), and the expression levels of the Osm and Osmr genes were measured. Relative gene expression levels were calculated by correcting for inter-sample ratios using the expression level of the Gapdh gene as a housekeeping gene (Figure 2). Increased expression of the Osm and Osmr genes was also confirmed in the MC903 AD model compared to the control group.

[0111] 1.2.3 Tests using a human AD model Comprehensive gene expression levels in human skin tissue were analyzed using the RNA-seq method. Skin tissue was collected from lesional and non-lesional areas of AD patients, as well as from healthy individuals, using a 1 mm punch biopsy. RNA was extracted from the skin tissue, and a sequencing library was prepared. Subsequently, the base sequence was determined using the HiSeq 2500 sequencing system (Illumina), and gene expression levels (TPM) were analyzed (Figure 3). Increased expression of the Osm and Osmr genes was confirmed in skin tissue collected from AD patients, particularly in lesional skin tissue.

[0112] (1.3 Attenuation of skin inflammation by knockout of Osm and Osmr genes) Osm knockout mice and Osmr knockout mice were created using the CRISPR-Cas9 method. The MC903-coated AD model was applied to each knockout mouse and the control group (WT mice) to induce dermatitis symptoms. The thickness of the auricle was measured over time every other day using a caliper (Mitutoyo) and the changes were compared (Figure 4). It was confirmed that the increase in auricle thickness was smaller in the Osm knockout mice and Osmr knockout mice compared to the control group.

[0113] Next, we analyzed the relationship between dermatitis symptoms caused by MC903 application and the expression levels of the type 2 cytokine Il13 gene, which is associated with atopic dermatitis, and the Lor gene, which is associated with the skin barrier. WT mice and Osm knockout mice were treated with ethanol solvent or MC903 solution every 12 days, and then ear samples were collected and comprehensive gene expression analysis was performed using RNA-seq (Figure 5).

[0114] (1.4 Induction of scratching behavior by subcutaneous administration of recombinant Osm) 10 μL of 2.5 μg recombinant mouse Osm (rmOsm) (Cell Signaling), physiological saline (negative control), or 10 μM BAM8-22 peptide (Abcam) (positive control) that induces itching was administered subcutaneously to the occipital region of WT mice, and scratching behavior was evaluated using a MicroAct device (neuroscience) (Figure 6). It was confirmed that individuals administered with BAM8-22 peptide or rmOsm exhibited an increased number of scratching behaviors compared to individuals administered with physiological saline.

[0115] Next, mice in which the Osmr gene is specifically deleted in neurons involved in the neurotransmission of itching (Nav1.8-Cre:Osmr ｆｌｏｘ／ｆｌｏｘ ) and control group (Osmr ｆｌｏｘ／ｆｌｏｘ Mice were administered 10 μL of 2.5 μg rmOsm, and scratching behavior was evaluated using a MicroAct device (Figure 7). Scratching behavior was suppressed in mice lacking the Osmr gene.

[0116] [2. Preparation of Cyclic Peptides] (2.1 Preparation of Cyclic Peptide Libraries) Peptide libraries were constructed using a flexible in vitro translation (FIT) system (Hipolito, CJ & Suga, Curr Opin Chem Biol. 16, 196-203, 2012; Passioura, T. & Suga, Chemistry. 19, 6530-6536, 2013) with N-(2-chloroacetyl)-tryptophan (ClAc-W) as the initiator. The corresponding mRNA libraries were designed to have, in order, an AUG start codon (encoding ClAc-W), 4-15 NNK random codons (N is G, C, A, or U, and K is G or U), and a UGC codon encoding cysteine. The random codons encode proteinaceous amino acid residues. Following in vitro translation, a thioether bond was spontaneously formed between the acetyl chloride group of the N-terminal initiator ClAc-W residue and the sulfhydryl group of the downstream cysteine ​​residue.

[0117] (2.2 Selection of cyclic peptides that bind to human OSMR) Using the RaPID system (Hipolito, CJ & Suga; Passioura, T. & Suga, as described above), affinity selection of peptides that bind to the extracellular region of human OSMR was performed on the above library. mRNA library and tRNA charged with ClAc-W ｆＭｅｔ ＣＡＵ (ClAc-W-tRNA ｆＭｅｔ ＣＡＵ The mixture was prepared as described in previous reports (Hipolito, CJ & Suga; Passioura, T. & Suga, mentioned above).

[0118] A 4 μM mRNA library was ligated with a 1.5 μM puromycin linker using T4 RNA ligase at 25°C for 30 minutes. The DNA of the puromycin linker bound to the 3' constant region of the mRNA library. After purification by phenol-chloroform extraction and ethanol precipitation, a 1.4 μM mRNA-puromycin conjugate and a 250 μM ClAc-W-tRNA were obtained. ｆＭｅｔ ＣＡＵ This was used in a methionine-deficient FIT system to generate a peptide library. Next, an in vitro translation reaction was carried out at 37°C for 30 minutes, followed by a further incubation at 25°C for 12 minutes to promote mRNA-peptide complexation, and then incubation at 37°C for 30 minutes to promote peptide cyclization.

[0119] Next, the product was reverse transcribed using M-MLV Reverse Transcriptase, RNase H Minus, and Point Mutant (Promega) at 42°C for 1 hour to tag the mRNA-cDNA hybrid with the cyclic peptide. The product was first subjected to a negative selection process three times using Dynabeads Protein G (Thermo Fisher) to remove undesirable bead binders. After negative selection, the peptide-mRNA / cDNA solution was incubated with Dynabeads Protein G immobilized with the extracellular region of 200 nM human OSMR at 4°C for 30 minutes to select the peptide that binds to human OSMR (positive selection).

[0120] Subsequently, the peptide-mRNA / cDNA was isolated from the beads by incubation in PCR reaction buffer heated at 95°C for 5 minutes. The amount of eluted cDNA was measured by quantitative PCR. The remaining cDNA was amplified by PCR, purified, and the transcribed mRNA was used as a library in the next step. A series of enrichment processes, including library preparation, negative selection, and positive selection, were considered one round, and significant enrichment of cDNA was observed in the fifth round. The recovered cDNA was sequenced using a next-generation sequencer, Miseq (illumina).

[0121] (2.3 Chemical Synthesis of Cyclic Peptides) Following a known method (Ito, K. et al. Nature Commun. 2015), the cyclic peptides obtained from the selection were synthesized using the Fmoc solid-phase peptide synthesis (SPPS) method with a Syro Wave automated peptide synthesizer (Biotage). Specifically, after automated synthesis of the peptides, a chloroacetyl group for cyclization was attached to the N-terminal amino group of the resulting product. The peptides were cleaved with a solution of 92.5% trifluoroacetic acid (TFA), 2.5% water, 2.5% triisopropylsilane, and 2.5% ethanedithiol, and precipitated with diethyl ether. To carry out the cyclization reaction, the peptide pellet was dissolved in 10 mL of a 1:1 solution of water and DMSO / 0.1% TFA, triethylamine was added to adjust the pH to >8, and then incubated at 42°C for 1 hour. TFA was added to the reaction solution to acidify the peptide suspension and stop the cyclization reaction. Subsequently, the peptide was purified by reverse-phase HPLC (Shimazu) using a prominence LC-20AP system equipped with a 200-25 mm Chromolith Prep column (Merck), and the molecular weight was confirmed by MALDI-TOF mass spectrometry (Bruker Daltonics) using a PerkinElmer Sciex API 150EX (Sciex). As an alternative purification method, cyclic peptides were purified using a HyperSep SPE C18 column (ThermoFisher Scientific).

[0122] [3. Evaluation of Cyclic Peptides] (3.1 Evaluation of the Ability to Inhibit OSM Signaling) For the human keratinocyte cell line HaCaT, which is an endogenous OSMR-expressing cell, the pGL4.47 [luc2P / SIE / Hygro] vector (Promega) was introduced, and a stable expression cell line was obtained by hygromycin selection. The above vector can induce the expression of luciferase by activating STAT3. Using this cell line, the ability of each peptide obtained by selection to inhibit OSM signaling was evaluated. Specifically, the cell line treated with the peptide prepared at a predetermined dilution ratio for 24 hours was stimulated with 10 ng / mL recombinant human OSM (rhOSM) for 24 hours and subjected to a luciferase assay. From the luminescence intensity of luciferase, the ability of each peptide obtained by selection to inhibit OSM signaling was evaluated. As a result, it was found that a cyclic peptide having the following structure (hereinafter referred to as "OSMR7") (SEQ ID NO: 22) has OSM signal inhibitory activity.

[0123]

[0124] In OSMR7, a thioether bond is formed between the acetyl chloride group of the N-terminal Trp and the sulfhydryl group of the cysteine residue. That is, in the above structure, an acetyl group is bonded to the main chain amino group of the N-terminal Trp, and NH-CO-CH ２ -S forms a closed-ring structure. Fig. 8 shows the evaluation results of the ability of OSMR7 to inhibit OSM signaling.

[0125] Next, the effect of OSMR7 on the expression level of the SOCS3 gene was evaluated. The SOCS3 gene is a gene whose expression is induced downstream of the OSM signal. After the HaCaT cell line was treated with OSMR7 in a concentration-dependent manner for 24 hours and stimulated with 10 ng / mL rhOSM for 24 hours, the SOCS3 gene was quantified by qPCR (Fig. 9). It was shown that OSMR7 inhibits OSM signaling and suppresses the expression of the downstream SOCS3 gene.

[0126] [4. Selection of OSMR7 Analogues] To further improve the target affinity of OSMR7 for the oncostatin M receptor (OSMR), OSMR7 analogues were prepared and their affinity for OSMR was evaluated.

[0127] (4.1 Deep Mutational Scanning of OSMR7) A peptide library was constructed using a flexible in vitro translation (FIT) system with N-(2-chloroacetyl)-tryptophan (ClAcW) as the initiator, in the same manner as described above. The mRNA library was designed to contain the mRNA shown in Figure 10. The mRNA library was designed to have, in order, an AUG start codon (encoding ClAc-W), a nucleotide sequence corresponding to the OSMR7 sequence with one amino acid codon replaced by NNK (N is G, C, A, or U, and K is G or U), and a UGC codon encoding cysteine. The random codons encode proteinaceous amino acid residues. After in vitro translation, a thioether bond spontaneously formed between the acetyl chloride group of the N-terminal initiator ClAc-W residue and the sulfhydryl group of the downstream cysteine ​​residue.

[0128] (4.2 Selection of OSMR7 analogs that bind to human OSMR) Affinity selection of peptides that bind to the extracellular region of human OSMR was performed on the above library using the RaPID system in the same manner as described above. A 4 μM mRNA library was ligated with a 1.5 μM puromycin linker using T4 RNA ligase at 25°C for 30 minutes. The DNA of the puromycin linker bound to the 3' constant region of the mRNA library. After purification by phenol-chloroform extraction and ethanol precipitation, a 1.4 μM mRNA-puromycin conjugate and a 250 μM ClAc-W-tRNA were obtained. ｆＭｅｔ ＣＡＵThis was used in a methionine-deficient FIT system to generate a peptide library. Next, an in vitro translation reaction was carried out at 37°C for 30 minutes, followed by further incubation at 25°C for 12 minutes to promote the mRNA-peptide complex, and then incubation at 37°C for 30 minutes to promote peptide cyclization.

[0129] Next, the product was reverse transcribed using M-MLV Reverse Transcriptase, RNase H Minus, and Point Mutant (Promega) at 42°C for 1 hour to tag the cyclic peptide with the mRNA-cDNA hybrid. The product was first subjected to negative selection three times using Dynabeads Protein G (Thermo Fisher). After negative selection, the peptide-mRNA / cDNA solution was incubated with Dynabeads Protein G immobilized with the extracellular region of 200 nM human OSMR at 4°C for 30 minutes to perform positive selection.

[0130] Subsequently, the peptide-mRNA / cDNA was isolated from the beads by incubation once in PCR reaction buffer heated at 95°C for 5 minutes. The amount of eluted cDNA was measured by quantitative PCR. The remaining cDNA was amplified by PCR, purified, and transcribed into mRNA as a library for selection in the next round. The cDNA sequences recovered after the second round were analyzed using a next-generation sequencer Miseq (illumina). Figure 11 shows the occurrence rates of each OSMR7 analog, with the occurrence rate of the original OSMR7 sequence set to 100%. Based on Figure 11, cyclic peptides with the following structures (sequence numbers 40 and 41 from the upper left, and sequence numbers 42 and 43 from the lower left) were chemically synthesized. In OSMR7 mut6 and OSRM7 mut7, n is D-Asn and d is D-Asp. In the following structure, an acetyl group is bonded to the main chain amino group of the N-terminal Trp, resulting in NH-CO-CH ２ It forms a ring-closing structure with -S. Similarly, other peptides containing the substructures represented by SEQ ID NOs: 2-21 were also chemically synthesized.

[0131]

[0132] (4.3 Chemical Synthesis of OSMR7 Analogues) Selected OSMR7 analogues were synthesized by Fmoc solid-phase peptide synthesis (SPPS) using a Syro Wave automated peptide synthesizer (Biotage) in accordance with known methods, similar to the method described above. Specifically, after automated peptide synthesis, a chloroacetyl group for cyclization was attached to the N-terminal amino group of the obtained product. The peptides were cleaved with a solution of 92.5% trifluoroacetic acid (TFA), 2.5% water, 2.5% triisopropylsilane, and 2.5% ethanedithiol, and precipitated with diethyl ether. To carry out the cyclization reaction, the peptide pellet was dissolved in 10 mL of a 1:1 solution of water and DMSO / 0.1% TFA, triethylamine was added to adjust the pH to >8, and the mixture was incubated at 42°C for 1 hour. TFA was added to the reaction solution to acidify the peptide suspension and stop the cyclization reaction. Next, the peptides were purified by reverse-phase HPLC (Shimazu) using a prominence LC-20AP system equipped with a 200-25 mm Chromolith Prep column (Merck), and their molecular weight was confirmed by MALDI-TOF mass spectrometry (Bruker Daltonics) using a PerkinElmer Sciex API 150EX (Sciex). As an alternative purification method, cyclic peptides were purified using a HyperSep SPE C18 column (ThermoFisher Scientific).

[0133] [5. In vitro evaluation of cyclic peptides] (5.1 Binding evaluation) To confirm the ability of the obtained peptides to inhibit OSM signal transduction, a binding evaluation with OSMR was performed. The binding evaluation was analyzed by surface plasmon resonance. Human OSMR with an Fc tag was immobilized on a Protein G chip (Cytiva) according to the standard immobilization protocol specified by Biacore 8K (Cytiva). The composition of the running buffer was as follows: 0.05 M Tris-HCl, 0.15 M NaCl, 0.05% (v / v) Tween 20, 0.1% (v / v) DMSO. Peptides prepared at a predetermined concentration were injected into the chip for analysis. A 1:1 binding fitting analysis was applied on the Biacore evaluation software to determine the k ｏｎ , k ｏｆｆ , K Ｄ values. The results are shown in the following table. The amino acid sequences in the table are SEQ ID NO: 1, 7, 8, 16, and 19 in order from the top. Other peptides containing the partial structures represented by SEQ ID NOs: 2 to 21 also showed binding affinity comparable to that of OSMR7.

[0134]

[0135] (5.2 OSM signal transduction inhibition ability evaluation) In the same manner as described above, the pGL4.47 [luc2P / SIE / Hygro] vector (Promega) was introduced into the human keratinocyte cell line HaCaT, which is an endogenous OSMR-expressing cell, and a stable expression cell line was obtained by hygromycin selection. The ability of the peptides to inhibit OSM signal transduction was evaluated using this cell line. The results are shown in FIG. 12. For all selected OSMR7 analogs, it was confirmed that they had higher inhibitory activity compared to the original OSMR7 (IC ５０ : 1.9 μM).

[0136] Next, using the same method as described above, we evaluated the effect on SOCS3 gene expression levels of OSMR7 analogs (OSMR7_Mut7 and OSMR7_Mut15) that showed particularly high binding affinity to OSMR. The results are shown in Figure 13. It was shown that OSMR7_Mut7 and OSMR7_Mut15 inhibited OSM signaling and significantly suppressed the expression of downstream SOCS3 genes.

[0137] (5.3 Cytotoxicity Evaluation) Cytotoxicity was evaluated for OSMR7 analogs (OSMR7_Mut7 and OSMR7_Mut15) that showed particularly high binding affinity to OSMR. HaCaT cell lines were treated with each cyclic peptide in a concentration-dependent manner for 24 hours, and cell viability was evaluated using WST-8 reagent (Dojin Chemical) after 24 hours of stimulation with 10 ng / mL rhOSM (Figure 14). High cell viability was observed over a wide range of cyclic peptide concentrations.

[0138] [6. In vivo evaluation of cyclic peptides] (6.1 Suppressive effect of cyclic peptides on atopic dermatitis pruritus and immune response suppression) Mice (hOSMR-KI) were created in which the mouse OSMR gene locus was replaced with the human OSMR gene sequence, and the suppressive effect of the cyclic peptide (OSMR7_Mut7), which showed the highest OSM signaling inhibitory activity in the above test, on atopic dermatitis pruritus was verified.

[0139] First, 10 μL of 2.5 μg of rhOSM protein dissolved in physiological saline was administered subcutaneously to the occipital region of hOSMR-KI, and the onset of atopic dermatitis pruritus was confirmed (Figure 15(A)). hOSMR-KI administered with physiological saline was used as a negative control. Scratching behavior was evaluated using a MicroAct device (neuroscience).

[0140] Next, 24 nmol of OSMR7_Mut7 dissolved in a solvent consisting of 5% DMSO and 95% physiological saline was subcutaneously administered to hOSMR-KI mice two hours before subcutaneous administration of rhOSM, and the number of rhOSM-induced scratching behaviors was compared with that of a control group administered only the solvent (Figure 15B). As a result, it was confirmed that the number of scratching behaviors decreased with the administration of OSMR7_Mut7. This suggests that the cyclic peptide or a pharmaceutically acceptable salt thereof according to this embodiment suppresses atopic dermatitis symptoms.

[0141] (6.2 Evaluation of the efficacy of peptides in an atopic dermatitis model) Mice were created in which the mouse Osm gene locus was replaced with the human OSM gene sequence and the mouse Osmr gene locus was replaced with the human OSMR gene sequence (hOSM-KI / hOSMR-KI), and the efficacy of OSMR7_Mut7 was evaluated using the MC903 application model. When atopic dermatitis was induced in both ears of hOSM-KI / hOSMR-KI mice using the MC903 model, a drug consisting of the following composition (250 nmol of OSMR7_Mut7, 5% DMSO, 47.5% methanol, 47.5% ethanol) was simultaneously applied to the auricle of the hOSM-KI / hOSMR-KI mice at 12-day intervals. The degree of inflammation was evaluated by measuring the thickness of the auricle (Figure 16). As a result, compared to a negative control group treated with a solvent consisting of 5% DMSO, 47.5% methanol, and 47.5% ethanol, it was confirmed that the increase in auricle thickness was suppressed in individuals treated with OSMR7_Mut7. This suggests that transdermal administration of the cyclic peptide or a pharmaceutically acceptable salt thereof according to this embodiment can suppress atopic dermatitis symptoms.

Claims

1. A peptide, or a pharmaceutically acceptable salt thereof, comprising a substructure having an amino acid sequence selected from the group consisting of (1) and (2) below.(1) An amino acid sequence represented by the following formula (I): RYRYYGHNLIAYGFY (I) (Sequence ID 1) (2) An amino acid sequence in which 1 to 6 amino acids are substituted in the amino acid sequence represented by the above formula (I), with N-terminal arginine as the first amino acid residue, the first amino acid residue may be substituted with a basic amino acid other than arginine and histidine, the second amino acid residue may be substituted with an aromatic amino acid other than tyrosine and histidine, the third amino acid residue may be substituted with a basic amino acid other than arginine and histidine, the fourth amino acid residue may be substituted with an aromatic amino acid other than tyrosine and histidine, the fifth amino acid residue may be substituted with an aromatic amino acid other than tyrosine and histidine or an amino acid containing a hydroxyl group, and the sixth amino acid residue may be substituted with alanine or its analogue, or a glycine analogue. The seventh amino acid residue may be substituted with an amino acid other than cysteine, lysine, proline, arginine, threonine, valine, and tryptophan; the eighth amino acid residue may be substituted with aspartic acid, glycine, tyrosine, phenylalanine, serine, histidine, glutamic acid, glutamine, alanine, leucine, or their analogues, or an asparagine analogue; the ninth amino acid residue may be substituted with an amino acid other than glycine, proline, and tryptophan; the tenth amino acid residue may be substituted with a branched-chain amino acid other than isoleucine; the eleventh amino acid residue may be substituted with an amino acid other than glycine, proline, and tryptophan; the twelfth amino acid residue may be substituted with a tyrosine analogue or a phenylalanine analogue; the thirteenth amino acid residue may be substituted with alanine, its analogue, or a glycine analogue. An amino acid sequence in which the 14th amino acid residue may be substituted with histidine, leucine, tyrosine, tryptophan, or analogs thereof, or an analog of phenylalanine, and the 15th amino acid residue may be substituted with an aromatic amino acid other than tyrosine and histidine.

2. In the amino acid sequence in (2) above, the first amino acid residue may be replaced with an arginine analog, the second amino acid residue may be replaced with tryptophan or its analog, a phenylalanine analog, or a tyrosine analog, the third amino acid residue may be replaced with an arginine analog, the fourth amino acid residue may be replaced with phenylalanine or its analog, or a tyrosine analog, the fifth amino acid residue may be replaced with a tyrosine analog or a phenylalanine analog, the sixth amino acid residue may be replaced with a glycine analog, the seventh amino acid residue may be replaced with asparagine, aspartic acid, glycine, glutamine, serine, tyrosine, glutamic acid, isoleucine, alanine or their analogs, or a histidine analog, and the eighth amino acid residue may be replaced with glycine or its analog, or an asparagine analog. The ninth amino acid residue may be substituted with glutamine, glutamic acid, valine, isoleucine, lysine, arginine, asparagine, histidine, or an analog thereof, or an analog of leucine; the tenth amino acid residue may be substituted with valine, or an analog thereof, or an analog of isoleucine; the eleventh amino acid residue may be substituted with threonine, serine, lysine, glutamine, leucine, asparagine, arginine, valine, histidine, aspartic acid, isoleucine, or an analog thereof, or an analog of alanine; the thirteenth amino acid residue may be substituted with an analog of glycine; the fourteenth amino acid residue may be substituted with tyrosine, or an analog thereof, or an analog of phenylalanine; and the fifteenth amino acid residue may be substituted with an analog of tyrosine or an analog of phenylalanine. The peptide according to claim 1, or a pharmaceutically acceptable salt thereof.

3. A peptide, or a pharmaceutically acceptable salt thereof, comprising a substructure having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21.

4. A cyclic peptide according to claim 1, wherein the substructure is included in the cyclic structure, or a pharmaceutically acceptable salt thereof.

5. The peptide according to claim 4, or a pharmaceutically acceptable salt thereof, wherein the substructure contains an aromatic amino acid at its N-terminus, and the substructure contains an amino acid having a sulfhydryl group at its C-terminus relative to the aromatic amino acid located at its N-terminus, and the N-terminus aromatic amino acid and the amino acid having the sulfhydryl group bond to form a cyclic structure.

6. The peptide according to claim 4, represented by formula (II), or a pharmaceutically acceptable salt thereof. (In formula (II) above, partial structure represents the partial structure, X １ Xaa and Xaa are each an amino acid independently. ２ OH, NH ２ , or (Xaa') ｒ (Xaa' is the aforementioned X １ (and Xaa are independent amino acids), where n and m are independent integers from 0 to 5, and r is an integer from 1 to 20.) 7. In equation (II) above, X １ The peptide according to claim 6, wherein n and m are 0, and n and m are 0, or a pharmaceutically acceptable salt thereof.

8. In the formula (II), X １ is tryptophan, n and m are 0, X ２ is (Xaa'), ｒ r is 1 and Xaa' is glycine, the peptide according to claim 6, or a pharmaceutically acceptable salt thereof.

9. The peptide is the peptide according to claim 4, represented by formula (III), or a pharmaceutically acceptable salt thereof. (In formula (III) above, partial structure represents the partial structure, X ２ OH, NH ２ , or (Xaa') ｒ (Xaa' is an amino acid, and r is 1.) 10. The peptide according to any one of claims 1 to 3, wherein the number of amino acid residues forming the peptide is 15 to 30, or a pharmaceutically acceptable salt thereof.

11. The peptide according to claim 6, or a pharmaceutically acceptable salt thereof, wherein in formula (II), the partial structure is an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21.

12. The peptide according to claim 9, or a pharmaceutically acceptable salt thereof, wherein in formula (III), the partial structure is an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 21.

13. A peptide, or a pharmaceutically acceptable salt thereof, comprising any of the following structures: (However, in the above structure, n means D-Asn, d means D-Asp, X ２ OH, NH ２ , or (Xaa') ｒ (Xaa' is an amino acid, and r is 1.) 14. X ２ (Xaa') ｒ (Xaa' is an amino acid), and the above (Xaa') ｒ A peptide according to any one of claims 6 to 9 and 11 to 13, wherein the N-terminus of is bonded to the carbonyl group of formula (II), or a pharmaceutically acceptable salt thereof.

15. A peptide according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, that binds to the oncostatin M receptor.

16. A peptide according to any one of claims 1 to 3, having OSM signal inhibitory activity, or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a peptide according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

18. The pharmaceutical composition according to claim 17, used for the treatment or prevention of atopic dermatitis.

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