Melanocyte-regulating peptides

Abstract

To provide peptides having the ability to regulate melanogenesis, either promoting or reducing the production of melanin, and the ability to inhibit the proliferation of malignant melanocytes, pharmaceutical compositions and cosmetic compositions comprising the peptides as active ingredients, and their use in therapy and cosmetics.SOLUTION: Provided are peptides having a sequence with at least 85% identity with a specific sequence, the peptides regulating melanocyte activity in terms of proliferation and production of melanin, and being useful not only in the treatment of melanomas but also in the cosmetic treatment of cutaneous hyperpigmentation or hypopigmentation.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of European Patent Application No. 19382674.0 filed on August 2, 2019. It asserts the interests of

[0002] The present invention relates generally to the field of melanocyte-associated disorders. In particular, the present invention relates to melanin The ability to regulate the formation of melanocytes, promote or decrease melanin production, and inhibit the proliferation of malignant melanocytes. Peptides having the ability to inhibit proliferation, pharmaceutical compositions and chemical compounds containing them as active ingredients The present invention relates to cosmetic compositions and their use in therapeutic and cosmetic applications. [Background technology]

[0003] Melanocytes produce pigment in the skin, eyes, hair, nasal passages, and hair through a process called melanogenesis. It produces melanin, a pigment found in the inner ear and the brain. This melanogenesis occurs when the pigment already present in the brain is converted into melanin. This results in long-lasting pigmentation, in contrast to pigmentation resulting from the oxidation of lanin.

[0004] Both basal and activated levels of melanogenesis exist, and are generally found in fair-skinned people. have a low basal level of melanin production. Exposure to UV-B radiation induces an increase in melanin production. The purpose of melanin production is to protect the subcutaneous tissue, the layer beneath the skin, from damage caused by UV-B radiation. Melanin is black in color and absorbs most of the UV-B light. Prevents penetration of the epidermis.

[0005] During a person's lifetime, there are obvious changes in skin color, and thus, for example, the face of an elderly person, It is known that age spots appear on the skin of the chest and hands, which are obvious signs of aging. Continuous overexposure to UV radiation can lead to the appearance of signs of skin aging at a much earlier age. Photoaging is characterized by the appearance of age spots, especially in areas of the skin that have been overexposed to UV radiation. Not only does it cause accelerated skin aging known as hyperpigmentation, but it also causes cancerous lesions or melanoma. It may also lead to the formation of cysts.

[0006] In areas of human skin, the density of melanin in melanocytes is greater than in the surrounding area, As a result, the affected areas are often darker in color than the rest of the person. These are known as hyperpigmented areas. Some of the causes of hyperpigmentation include hormonal changes, liver Macular spots, lentigines, localized albinism, Addison's disease, UV sensitivity due to drugs that enhance the effects of radiation hyperpigmentation as a result of skin irritation (phototoxicity), or inflammatory lesions. Hair removal-related age spots belong to this last type of hyperpigmentation and can last for years. It's a stain you'll get.

[0007] Areas of a person's skin may also have areas with a lower melanin density than the surrounding areas. Pityriasis versicolor, tinea versicolor, and post-inflammatory effects are common causes of pigment loss. The attenuation of this effect may be due to either aging and / or photoaging, hormonal disorders, or post-inflammatory processes. In particular, topical application has been shown to restore pigmentation in areas affected by vitiligo. This is of interest to the cosmetics and pharmaceutical sectors.

[0008] Pigmentation disorders are a global problem. Despite their prevalence, pigmentation disorders It remains difficult to treat.

[0009] The main approaches for the treatment of hyperpigmentation disorders are primarily due to overactive melanocytes. Preventing melanin production or promoting its removal from the epidermis by increasing epidermal cell turnover Based on the advancement of tyrosinase, a rate-limiting enzyme involved in melanin synthesis, several Medications are currently used to treat hyperpigmentation disorders with some success. These agents include hydroquinone, kojic acid (also known as "KA"), and These include rubutin, mequinol, and azelaic acid. Contact dermatitis can occur when using these drugs. These drugs are common side effects that occur in up to 15% of patients and limit their use. The effectiveness of topical retinoids varies widely among patients. This reduces epidermal melanin and increases epidermal turnover, thereby improving melanin distribution. However, a frequent adverse effect is irritant dermatitis, and When high-concentration topical retinoids are prescribed for darker skin types, the resulting Be aware that irritation may result in erythema, scaling, and further post-inflammatory hyperpigmentation. Laser treatments can be effective for hyperpigmentation. However, this , there is an increased baseline of epidermal melanin targeted at these wavelengths, compared This poses significant problems in darker-skinned patients.

[0010] Hypopigmentation disorders also involve inflammatory and autoimmune etiologies, and local corticosterone Idiopathic and immunomodulatory drugs may be useful in treatment regimens. Post-inflammatory hypopigmentation is usually These same topical agents are clinically significant after the inflammatory process has resolved, so they may be effective in this late stage. Phototherapy, including but not limited to psoralens, may not be beneficial in some cases. +UVA (oral or topical), psoralens and natural sunlight, UVB, narrow-band UVB and 308 nm excimer lasers are used to treat both hypopigmentation and depigmentation. Hypopigmentation disorders (e.g., vitiligo) are characterized by the complete absence of melanocytes in the interfollicular epidermis. Therefore, treatment can be particularly difficult. The purpose is to mobilize or transplant.

[0011] Therefore, despite these efforts, we have not been able to efficiently regulate melanocyte activity. and, as a result, further molecules that may be efficient in the treatment of pigmentation disorders. There remains a need to develop (peptides). Summary of the Invention [Problem to be solved by the invention]

[0012] The present inventors have found that the peptides of the sequences of SEQ ID NOs: 1 and 2 effectively regulate melanocyte activity. I found that.

[0013] On the other hand, the present inventors have surprisingly found that the peptide of the present invention is involved in the melanogenesis pathway. Therefore, some peptides may be indicators of melanocyte activation. Although other peptides such as F22 and F29 stimulated the production of melanin, Even more remarkable is that the peptides of the present invention dramatically reduced the was more efficient in regulating melanin production when compared to other compounds. In this regard, KA, a commonly used treatment for hyperpigmentation, was used at a concentration of 1 μM. In this case, the reduction is substantially lower than that achieved with the peptide of the present invention at the same concentration. These data therefore support the effect of the peptides of the present invention on melanin production. Not only do they support efficacy, but they are available with the latest technology currently used for the same purpose. It also shows that it is more efficient than other compounds.

[0014] On the other hand, the present inventors have found that these peptides not only promote melanin formation but also cell proliferation. As shown in Table 2, the peptides of the present invention were found to regulate melanocyte activity. in inhibiting cancer cell proliferation, particularly melanoma cell lines, including metastatic melanoma cell lines. It was active. [Means for solving the problem]

[0015] Thus, in a first aspect, the present invention provides a method for producing at least one of the individual sequences of SEQ ID NO: 1 or 2 below. having an amino acid sequence with at least 85% identity to: (Trp) m -(Asn) n -Lys-Gly-Thr-Ile-Leu-Lys-A la-Ser-Val-Asp-Tyr-Ile-Arg-Lys-(Leu) p -(G ln) q( Sequence number 1) (Arg) mx -(Arg) nx -Arg-Arg-Phe-Asn-Ile-Asn -Asp-Arg-Ile-Lys-Glu-Leu-Gly-Thr-Leu-(Il e) px -(Pro) qx( Sequence number 2) (In the formula, "m", "n", "p", and "q" represent integers and are selected from 0 and 1; "m x "," "n x ", "p x " and "q x" represents an integer and is selected from 0 and 1; The C-terminus corresponds to -C(O)R4; The N-terminus corresponds to -NHR5; R4 is -OH and -NR 17 R 18 is a group selected from the group consisting of: R5 is -H, (C1-C 20 ) alkyl, and halogen, (C1-C 10 )Archi -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 , and -CO2 R 12 (C1-C 10 ) alkyl is a group selected from the group consisting of: R 17 and R 18 is -H and (C1-C 10 ) alkyl, and halogen, (C1- C 10 )Alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 、 and -CO2R 12 (C1-C 10 ) alkyl); optionally, The alpha carbon atom of the amino acid at position "i" in the peptide sequence and the alpha carbon atom of the amino acid at position "i+4" or "i a linker of the following formula (I) connecting the alpha carbon atom of the amino acid located at the "+7" position to the Biradical "L", -[(R1) a -(R2)-(R3) b ] c -(I) [In the formula, "a" and "b" are the same or different and are 0 or 1; "c" consists of 1 to 10; R1 and R3 are (C1-C 10 ) alkyl; halogen, (C1-C 10 ) alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 , and -CO2R1 substituted with one or more groups selected from the group consisting of (C1-C 10 ) alkyl;( C2-C 10 ) alkenyl; halogen, (C1-C 10 ) Alkyl, -OR6, -NR7 R8, -SR9, -SOR 10 , -SO2R 11 , and -CO2R 12 Selected from the group consisting of (C2-C 10 ) alkenyl; (C2-C 10 )a alkynyl; and halogens (C1-C 10 )Alkyl, -OR6, -NR7R8, -S R9, -SOR 10 , -SO2R 11 , and -CO2R 12 1 selected from the group consisting of or substituted with multiple groups (C2-C 10 ) alkynyl; It is a biradical; R2 is -O-, C(=O), C(=O)NR 13 , C(=O)O, S(=O), S( =O)2, NR 14 , (C1-C 10 ) alkyl, (C2-C 10 ) alkenyl, (C2 -C 10 ) alkynyl, -NR 15 -NR 16 -, -N=N-, -SS-, and 3~1 Known ring systems containing 4 members and 1 to 3 rings (wherein each of the rings is saturated, partially unsaturated, or aromatic; the rings may be isolated, partially or fully fused; The members forming the known ring systems are -CH-, -CH2-, -NH-, -N-, -S selected from the group consisting of -H-, -S-, and -O-; and The ring system may optionally be substituted with halogen, —OH, —NO, (C-C 10 ) alkyl, (C 1-C 10 ) haloalkyl, and (C1-C 10 ) alkyl-O- and a biradical selected from the group consisting of: Yes; and R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13、 R 14、 R 15、 and R 16 is -H and (C1-C 10 ) alkyl, ;and The amino acids linked by the linker are of formula (II) [ka] {In the formula, R 19 is (C1-C 10 ) alkyl, (C2-C 10 ) alkenyl, (C2-C 10 ) alkynyl, and known ring systems containing 3 to 14 members and 1 to 3 rings (wherein each of the rings is saturated, partially unsaturated, or aromatic; the rings may be isolated, partially or fully fused; The members forming the known ring systems are -CH-, -CH2-, -NH-, -N-, -S -H-, -S-, and -O-) and a peptide containing the compound {which is a hydroxyl group}, or a pharmaceutically or cosmetically acceptable salt thereof. Provide.

[0016] In a second aspect, the present invention provides a cosmetically effective or therapeutically effective amount of a compound as defined in the first aspect of the invention. Cosmetic compositions containing acceptable cosmetic or pharmaceutical excipients and / or carriers together with the peptides to be treated. A pharmaceutical composition is provided.

[0017] In a third aspect, the present invention provides a compound as defined in the first aspect of the invention for use as a medicament. The present invention provides a peptide or a pharmaceutical salt thereof, or a pharmaceutical composition according to the second aspect of the present invention. This aspect relates to the use of a compound as defined in the first aspect of the invention in the manufacture of a medicament for treating a disease. or a pharmaceutical composition according to the second aspect of the present invention. This aspect also relates to a method for treating a disease, comprising: a therapeutically effective amount of a peptide as defined in the first aspect of the present invention or a pharmaceutical salt thereof, A method comprising administering the pharmaceutical composition of the second aspect of the invention to a subject in need thereof. Alternatively, the compound may be formulated as follows:

[0018] In a fourth aspect, the present invention provides a method for treating cancer, comprising administering to a subject a therapeutically effective amount of a compound as defined in the first aspect of the invention for use in the treatment of cancer. a peptide or a pharmaceutical salt thereof, or a pharmaceutical composition as defined in the second aspect of the present invention. This aspect provides a method for treating cancer comprising administering to a subject a compound according to the first aspect of the present invention. a peptide as defined in the first aspect of the invention or a pharmaceutical salt thereof, Alternatively, the present invention can be formulated as a pharmaceutical composition for use in the treatment of cancer. The method comprises administering to a subject a therapeutically effective amount of a peptide or peptides as defined in the first aspect of the invention. or a pharmaceutical salt thereof, or a pharmaceutical composition as defined in the second aspect of the present invention, to a patient in need thereof. Alternatively, it can be formulated as a method comprising administering to a subject.

[0019] In a fifth aspect, the present invention also provides a method for modulating melanogenesis, in particular the production of melanin. A peptide as defined in the first aspect of the invention or a compound thereof for reducing or increasing There is provided a non-therapeutic use of a cosmetic salt or a cosmetic composition as defined in the second aspect of the present invention.

[0020] In a final aspect, the present invention provides a method for treating hyperpigmentation or hypopigmentation in a subject in need thereof. A cosmetic method for treating hypoglycemia, comprising administering to a subject a peptide or peptides as defined in the first aspect of the invention. or a cosmetic salt thereof, or a cosmetic composition as defined in the second aspect of the present invention, and applying the composition to areas suffering from hyperpigmentation or hypopigmentation.

[0021] In a further aspect, the present invention provides a method for the preparation of a peptide as defined in the first or second aspect of the present invention. (b) a combination of a compound or a pharmaceutical salt thereof with a therapeutic agent, particularly an anti-cancer agent; and (b) use as a pharmaceutical. a compound as defined in the first or second aspect of the invention for use in the treatment of cancer, more particularly in the treatment of (c) a combination of a defined peptide or a pharmaceutical salt thereof with a therapeutic agent, particularly an anti-cancer agent; Administering to a subject simultaneously, sequentially, or separately with an anti-cancer drug for prophylaxis or treatment A peptide as defined in the first or second aspect of the invention for use in combination therapy comprising or a pharmaceutical salt thereof; (d) a peptide or a drug thereof as defined in the first or second aspect of the present invention. Anti-cancer agents for uses including the prevention or treatment of cancer, for use in combination therapy with a chemical salt ;to provide. [Brief explanation of the drawings]

[0022] [Figure 1] Figure 1 shows the percentage of melanin in treated versus untreated melanoma cells. As a positive control, kojic acid (KA) was used at different concentrations (0.1, 1 and 10 μM). DETAILED DESCRIPTION OF THE INVENTION

[0023] Detailed Description of the Invention All terms used herein in this application are of the art unless otherwise specified. Certain terms used in this application are to be understood in their ordinary and known sense. The specific definitions are as follows, with the explicitly stated definitions providing broader definitions. Unless otherwise stated, it is intended that all such provisions apply uniformly throughout the specification and claims.

[0024] For purposes of this invention, any given range shall include both the lower and upper endpoints of that range. include.

[0025] As described above, the present invention relates to a sequence having at least 85% identity with SEQ ID NO: 1 or 2. The present invention provides a peptide comprising:

[0026] In the present invention, the term "identity" refers to the degree of identity when the sequences are optimally aligned. It refers to the percentage of residues that are identical in two sequences. wherein a position in the first sequence is filled by the same amino acid residue as the corresponding position in the second sequence. If so, the sequences show identity at that position. The level (or "percent sequence identity") is the number of identities the sequences share relative to the size of the sequences. The percent sequence identity is measured as the ratio of the number of identical positions (i.e., percent sequence identity = (number of identical positions) / total number of positions) × 100).

[0027] Several tools for quickly obtaining optimal alignments and calculating identity between two or more sequences. Several mathematical algorithms are known and several software programs are available. Examples of such programs include, among others, amino acid sequence analysis For MATCH-BOX, MULTAIN, GCG, FASTA and ROBUST projects Preferred software analysis programs include ALIGN, CLU, STAL W, and BLAST programs (e.g., BLAST2.1, BL2SEQ, and and their later versions).

[0028] For amino acid sequence analysis, use BLOSUM matrices (e.g., BLOSUM45, BLOS UM50, BLOSUM62, and BLOSUM80 matrices), Gonnet matrix, or PA M matrix (e.g., PAM30, PAM70, PAM120, PAM160, PAM250 , and PAM350 matrix) are used to determine identity.

[0029] The BLAST program searches for sequences in a database (e.g., GenSeq). Alignment is performed against multiple sequences or between two selected sequences using BL2SEQ. The BLAST program provides an analysis of at least two amino acid sequences. The program is preferably integrated into the BLAST program operation, and is suitable for DUST or SEG programs. Preferably, the image is modified by a low-complexity filtering program such as a filter program. If a gap existence cost (or gap score) is used, the gap existence cost is Preferably, it is set between about -5 and -15. The same gap parameter can be adjusted as needed. It can be used with other programs. The principle is explained in, for example, Altschul et al., "Basic local al ignment search tool”,1990,J.Mol.Biol,v.2 15, pages 403-410.

[0030] For multiple sequence analysis, the CLUSTAL W program can be used. AL W programs are run using the "dynamic" (as opposed to "fast") setting. The amino acid sequence is preferably a variable number in the BLOSUM matrix depending on the level of identity between the sequences. The CLUSTAL W program and its basic operating principles are: For example, Higgins et al., “CLUSTAL V: improved s oftware for multiple sequence alignment” ,1992,CABIOS,8(2),pages189-191 do.

[0031] As used herein, the term "pharmaceutically or cosmetically acceptable salt" refers to a salt that is pharmaceutically or cosmetically acceptable in accordance with sound medical practice. within the scope of reasonable judgment, without excessive toxicity, irritation, allergic reactions, etc., to humans and lower animals. Suitable for use in contact with tissue and commensurate with a reasonable benefit / risk ratio Pharmaceutically and cosmetically acceptable salts are well known in the art. Examples of physiologically and cosmetically acceptable non-toxic acid addition salts are hydrochloric, hydrobromic, phosphoric, sulfuric acid addition salts. Acid and inorganic acids such as perchloric acid, or acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, alcohol Salts of amino groups formed with organic acids such as tartaric acid, citric acid, succinic acid or malonic acid, or is a salt of an amino group formed by other methods used in the art, such as ion exchange. Other pharmaceutically and cosmetically acceptable salts include adipates, alginates, and alginates. Corbate, aspartate, benzenesulfonate, benzoate, bisulfate, phosphatase Urate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate salts, digluconates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucurons Glycerol, phosphate, gluconate, hemisulfate, heptanoate, hexahydrate Acid salt, hydroiodide, 2-hydroxy-ethanesulfonic acid, lactobionate, milk Salt, laurate, lauryl sulfate, malate, maleate, malonate, methane Sulfonic acid, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, urates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionate, phosphate, picrate, pivalate, propionate , stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate Salts derived from appropriate bases include benzoate, undecanoate, valerate, etc. Typical alkali metals or Salts of alkaline earth metals include sodium, lithium, potassium, calcium, magnesium, Further pharmaceutically and cosmetically acceptable salts include, where appropriate, non-toxic Ammonium, quaternary ammonium, halides, hydroxides, carboxylates , sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates, etc. and amine cations formed using the counterions:

[0032] (C1-C 10 The term alkyl refers to a saturated straight or branched alkyl group having 1 to 10 carbon atoms. refers to a branched alkyl chain. Illustrative non-limiting examples are methyl, ethyl, propyl, iso Propyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-pentyl and n-hexyl.

[0033] (C1-C 20 The term alkyl refers to a saturated straight or refers to a branched alkyl chain.

[0034] (C2-C 10 The term alkenyl contains 2 to 10 carbon atoms and includes one or more refers to a saturated straight or branched alkyl chain further containing a double bond of the formula: is ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.

[0035] (C2-C 10 The term alkynyl includes 2 to 20 carbon atoms and includes one or more refers to saturated straight or branched alkyl chains which further contain a triple bond of the formula: , ethynyl, 1-propynyl, 2-butynyl, 1,3-butadinyl, 4-pentynyl and 1-hexynyl.

[0036] The term "halogen" refers to five chemically related elements: fluorine (F), chlorine (Cl), ), bromine (Br), iodine (I), and astatine (At).

[0037] (C1-C 10 The term haloalkyl refers to (C1-C 10 ) one or more alkyl groups The number of hydrogen atoms may be one or more, preferably 1 to 6, and may be the same or different. Examples include, inter alia, trifluoromethyl. , fluoromethyl, 1-chloroethyl, 2-chloroethyl, 1-fluoroethyl, 2-fluoro Fluoroethyl, 2-bromoethyl, 2-iodoethyl, 2,2,2-trifluoroethyl , pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 2,2,3,3 -tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl Examples include 4-fluoropropyl, 4-fluorobutyl and nonafluorobutyl.

[0038] As used herein, the term "known" ring system refers to a ring system that is chemically feasible and known in the art. It is intended to refer to ring systems known in the art and therefore exclude chemically impossible ring systems.

[0039] According to the present invention, when a ring system is formed by "isolated" rings, the ring system may have 2, 3 or 4 rings. rings, which are joined via a bond from an atom of one ring to an atom of the other ring. The term "isolated" also encompasses embodiments in which the ring system has only one ring. Illustrative, non-limiting examples of known ring systems consisting of one ring are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutene and those derived from cyclopentenyl, phenyl, and cycloheptenyl.

[0040] According to the present invention, when a ring system has "fully fused" rings, the ring system has two or more atoms. means that the ring is formed by 2, 3 or 4 rings that are common to two adjacent rings Illustrative, non-limiting examples include 1,2,3,4-tetrahydronaphthyl, 1-naphthyl, 2 naphthyl, anthryl or phenanthryl.

[0041] According to the present invention, when a ring system is "partially fused", it means that the ring system is made up of three or four rings. and at least two of the rings are fully fused (i.e., two or more atoms is common to two adjacent rings), the remaining rings are connected to an atom of one ring by an atom of one fused ring This means that the bond is via a bond to

[0042] Unless otherwise specified, the amino acids forming the peptides of the present invention may have either the L- or D-configuration. It is possible.

[0043] The amino acids used in the construction of the peptides of the invention may be prepared by organic synthesis; or may be obtained by other routes, such as, for example, degradation of or isolation from natural sources. stomach.

[0044] In one embodiment of the first aspect of the invention the peptide has the sequence of SEQ ID NO: 24, 25 or 26. It is a peptide other than the sequence.

[0045] In one embodiment of the first aspect of the invention, optionally any of the embodiments provided above or below In combination with any one of the above, the peptide is a peptide in which m and n are the same. In another embodiment of the aspect, optionally in combination with any of the embodiments provided above or below. In combination, the peptide is one in which p and q are the same. In the embodiment, optionally in combination with any of the embodiments provided above or below, and n represents 1, and p and q represent 0. In another embodiment of the first aspect of the invention, any In the alternative, in combination with any of the embodiments provided above or below, m and n represent 0. and p and q represent 1.

[0046] In another embodiment of the first aspect of the invention, optionally in the embodiments provided above or below In combination with any of the states, the peptide is a linear peptide.

[0047] In the present invention, the term "linear peptide" is intended to include no "L" biradical. means.

[0048] In one embodiment of the first aspect of the invention, optionally any of the embodiments provided above or below The peptide may be selected from the group consisting of SEQ ID NO: 1, (In the formula, - if "m" and "n" are the same, then "p" and "q" are different; and - if m is 0 and n=p=1, then q is 1) It is a linear peptide consisting of:

[0049] In another embodiment of the first aspect of the invention, optionally in the embodiments provided above or below In combination with any of the above conditions, the peptide is a linear peptide consisting of SEQ ID NO: 1, Selected from the following peptides: - at least three of m, n, p and q are the same; or - if "m" is 0 and "n" is 1, then "p" is 0 and "q" is 0 or 1; or - if "m" is 0 and "n" is 1, then "p" is 0 or 1 and "q" is 1 do.

[0050] In one embodiment of the first aspect of the invention, optionally any of the embodiments provided above or below In combination with either x and n x are the same peptides. In another embodiment of one aspect, optionally any of the embodiments provided above or below. In combination with x and q x are the same peptides. In another embodiment, optionally in combination with any of the embodiments provided above or below. Let me x and n x represents 1, and p x and q x represents 0. Another embodiment of the first aspect of the present invention In an embodiment, optionally in combination with any of the embodiments provided above or below: m x and n x represents 0, and p x and q x represents 1.

[0051] In another embodiment of the first aspect of the invention, optionally in the embodiments provided above or below In combination with any of the above embodiments, the peptide or salt thereof may comprise an "L" linker where a=1. In another embodiment of the first aspect of the invention, optionally as provided above or below In combination with any of the preceding embodiments, the peptide or salt thereof may comprise an "L" linker where b=1. In another embodiment of the first aspect of the present invention, optionally as described above or below. In combination with any of the embodiments provided, the peptide or salt thereof may comprise an "L" group with c=1. In another embodiment of the first aspect of the present invention, the above or in combination with any of the embodiments provided below, the peptide or salt thereof may be =c=1 including the "L" linker.

[0052] In another embodiment of the first aspect of the invention, optionally in the embodiments provided above or below In combination with any of the above, the peptide or salt thereof may be 10 ) Alkyl; (C2-C 10 ) alkenyl; and (C2-C 10 ) from the group consisting of alkynyl The first aspect of the present invention includes an "L" linker that is a biradical independently selected from the group consisting of: In another embodiment of this aspect, optionally with any of the embodiments provided above or below. In combination, the peptide or salt thereof may be a peptide in which R1 and R3 are the same or different ( C1-C 10 ) alkyl.

[0053] In another embodiment of the first aspect of the invention, optionally in the embodiments provided above or below In combination with any of the above, the peptide or salt thereof may be (=O)NR 13 , C(=O)O, S(=O), S(=O)2, NR 14 , (C1-C1 0) Alkyl, (C2-C 10 ) alkenyl, (C2-C 10 ) alkynyl, -NR 15 -NR 16 -, -N=N-, -SS-, and a single ring of 3 to 6 members The Circle of Knowledge (The ring may be saturated, partially unsaturated, or aromatic; The members forming the known ring systems are -CH-, -CH2-, -NH-, -N-, -S selected from the group consisting of -H-, -S-, and -O-; and The ring system may optionally be substituted with halogen, —OH, —NO, (C-C 10 ) alkyl, (C 1-C 10 ) haloalkyl, and (C1-C 10 ) alkyl-O- and wherein the biradical is selected from the group consisting of It contains the "L" linker, which is a nucleotide.

[0054] In another embodiment of the first aspect of the invention, optionally in the embodiments provided above or below In combination with any of the above, the peptide or salt thereof may be 10 )Archi le, (C2-C 10 ) alkenyl, and (C2-C 10 ) alkynyl Another embodiment of the first aspect of the invention includes an "L" linker that is a biradical. In an embodiment, optionally in combination with any of the embodiments provided above or below: The peptide or salt thereof is a peptide in which R2 is (C2-C 10 ) containing an "L" linker that is alkenyl It is something that

[0055] In another embodiment of the first aspect of the invention, optionally in the embodiments provided above or below In combination with any of the above embodiments, the peptide or salt thereof may be Different (C1-C 10 ) alkyl, and R2 is represented by (C2-C 10 ) alkenyl and an "L" linker,

[0056] In another embodiment of the first aspect of the invention, optionally in the embodiments provided above or below In combination with any of the above embodiments, the peptide or salt thereof may be Different (C1-C 10 ) alkyl, and R2 is represented by (C2-C 10 ) alkenyl and an "L" linker where a=b=c=1.

[0057] In another embodiment of the first aspect of the invention, optionally in the embodiments provided above or below In combination with any of the above, the peptide or salt thereof may be 19 However, (C1-C 10 )Al Kill, (C2-C 10 ) alkenyl, and (C2-C 10 ) alkynyl In another embodiment of the first aspect of the present invention, the method is optionally selected from the above or below. In combination with any of the embodiments provided above, the peptide or salt thereof may comprise R 19 but,( C1-C 10 ) alkyl monoradical. In some embodiments, the present invention may be used in combination with any of the embodiments provided above or below. The peptide or salt thereof is R1, R3 and R 19 are the same or different (C1-C 10 ) alkyl, and R2 is represented by (C2-C 10 ) an "L" linker that is alkenyl It includes.

[0058] In another embodiment of the first aspect of the invention, optionally in the embodiments provided above or below In combination with any of the above embodiments, the peptide or salt thereof may also be such that R4 is -OH (i.e., In another embodiment of the first aspect of the present invention, Peptides or The salt is a compound in which R4 is -NR 17 R 18 and R 17 and R 18 means the same thing In another embodiment of the first aspect of the invention, optionally as provided above or below In combination with any of the embodiments, the N-terminus corresponds to -NH2. In another embodiment of the present invention, optionally in combination with any of the embodiments provided above or below. In addition, the C-terminus and N-terminus of the peptide of the present invention are -C(O)OH and -NH 2. In another embodiment of the first aspect of the invention, optionally as provided above or below In combination with any of the preceding embodiments, the C-terminus and N-terminus of the peptide of the present invention may each be are -C(O)NH2 and -NH2.

[0059] In another embodiment of the first aspect of the invention, optionally in the embodiments provided above or below In combination with any of the above embodiments, the C-terminus and N-terminus of the peptide of the present invention may be -C (O)OH and —NHR5, where R5 is (C1-C 20 ) alkyl and halogen , (C1-C 10 )Alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -S O2R 11 , and -CO2R 12 and substituted with one or more groups selected from the group consisting of (C1-C 10 ) alkyl).

[0060] In another embodiment of the first aspect of the invention, optionally in the embodiments provided above or below In combination with any of the above embodiments, the C-terminus and N-terminus of the peptide of the present invention may be -C (O) R4 and -NH2 (wherein R4 is -NHR 18 means R 18 is (C1-C1 0) alkyl, and halogen, (C1-C 10 ) alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 , and -CO2R 12 Selected from the group consisting of substituted with one or more groups (C1-C 10 ) alkyl (which is a base).

[0061] In another embodiment of the first aspect of the invention, optionally in the embodiments provided above or below In combination with any of the above embodiments, the C-terminus and N-terminus of the peptide of the present invention may be -C (O) R4 and -NH2 (wherein R4 is - NR 17 R 18 means R 17 and R 18 teeth , (C1-C 10 ) alkyl, and halogen, (C1-C 10 ) alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 , and -CO2R 12 Consists of substituted with one or more groups selected from the group (C1-C 10 ) alkyl is a group independently selected from

[0062] In another embodiment of the first aspect of the invention, optionally in the embodiments provided above or below In combination with any of the above embodiments, the linker biradical of formula (I) may be a peptide of the sequence SEQ ID NO: 1. the alpha carbon atom of the amino acid at position "i" in the peptide sequence and the peptide of SEQ ID NO: 1 The carbon atom is between the alpha carbon atom of the amino acid at position "i+7" in the amino acid sequence.

[0063] In another embodiment of the first aspect of the invention, optionally in the embodiments provided above or below The peptide or salt thereof may be selected from the group consisting of the amino acid sequences of SEQ ID NOs: 3 to 8, in combination with any of the above-mentioned embodiments. Selected from the group consisting of: [ka] (wherein "m", "n", "p", "q", "L" and "R 19 " refers to the preceding embodiment. (as defined in either

[0064] In another embodiment of the first aspect of the invention, optionally in the embodiments provided above or below In combination with any of the embodiments, the linker biradical of formula (I) may be a peptide of SEQ ID NO: 2 The alpha carbon atom of the amino acid located at position "i" in the sequence and the peptide sequence of SEQ ID NO:2 It is between the alpha carbon atom of the amino acid at position "i+7" in the

[0065] In another embodiment of the first aspect of the invention, optionally in the embodiments provided above or below In combination with any of the above, the peptide or salt thereof may be selected from the group consisting of the amino acid sequences of SEQ ID NOs: 9 to 16. Selected from the group consisting of: [ka] JPEG2025131623000004.jpg33170 (In the formula, "mx "," "n x ", "p x ", "q x ", "L" and "R 19 " precedes as defined in any of the embodiments).

[0066] In another embodiment of the first aspect of the invention, optionally in the embodiments provided above or below The peptide or salt thereof may be selected from the group consisting of SEQ ID NOs: 3 to 8 (wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R 3 and R 19 are the same or different (C1-C 10 ) alkyl, and R 2 is (C2-C 10 ) alkenyl) In another embodiment of the first aspect of the invention, the method optionally comprises the steps of any of the methods provided above or below. In combination with any of the embodiments, the peptide or salt thereof is selected from the group consisting of SEQ ID NOs: 3 to 8 (wherein R1 , R3 and R 19 are the same or different (C1-C 10 ) alkyl , R2 is (C2-C 10 ) alkenyl, and the C-terminus is -C(O)OH and -CONH 2, and the N-terminus is -NH2) be.

[0067] In another embodiment of the first aspect of the invention, optionally in the embodiments provided above or below In combination with any of the above, the peptide or salt thereof may be selected from the group consisting of SEQ ID NOs: 9 to 16 (wherein R1, R3 and R 19 are the same or different (C1-C 10 ) alkyl, R2 is (C2-C 10 ) alkenyl) In another embodiment of the first aspect of the invention, optionally as provided above or below In combination with any of the embodiments, the peptide or salt thereof is selected from the group consisting of SEQ ID NOs: 9 to 16, R1, R3 and R 19 are the same or different (C1-C 10 ) represented by alkyl and R2 is (C2-C 10 ) alkenyl, with the C-terminus being —C(O)OH and —CO and the N-terminus is -NH2) That is why.

[0068] In another embodiment of the first aspect of the invention, the peptide is selected from the group consisting of SEQ ID NOs: 17 to 23: a peptide having at least 85% identity to an amino acid sequence selected from the group consisting of: Pharmaceutical or cosmetic salts thereof: [ka] JPEG2025131623000006.jpg36170

[0069] In another embodiment of the first aspect of the invention, optionally in the embodiments provided above or below The peptide or salt thereof may be selected from the group consisting of SEQ ID NOs: 1 to 23 ("m", "n"), ”, “p”, “q”, “m x "," "n x ", "p x ", "q x ", L and R 19 is the above 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 1 7%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 9 A first aspect of the invention is a peptide having 7%, 98%, 99% or 100% identity In another embodiment of the present invention, optionally in combination with any of the embodiments provided above or below. In addition, the peptide or salt thereof is selected from the group consisting of SEQ ID NOs: 1 to 23 ("m", "n", "p", "q", "m x "," "n x ", "p x ", "q x ", L and R 19 In any of the above embodiments, is a peptide having 100% identity with any of the sequences of In one embodiment, optionally in combination with any of the embodiments provided above or below The two amino acid residues connected by the linker are then used to determine the degree of identity. These are not taken into account when performing alignment to determine the same position.

[0070] In one embodiment of the first aspect of the invention, optionally any of the embodiments provided above or below In combination with any of the above, the peptide of the first aspect may be used as a label, a drug or a cell membrane-permeable peptide. In another embodiment of the first aspect of the invention, any Optionally in combination with any of the embodiments provided above or below, the peptide may be In another embodiment of the first aspect of the invention, optionally as described above or below, In combination with any of the embodiments provided above, the label may be attached to the N-terminus or C-terminus of the peptide. is conjugated to

[0071] As used herein, a "label" refers to a variety of labels, including fluorescence, conductivity, radioactivity, size, etc. A label is a molecule or compound that can be detected by various methods. signals such as fluorescent labels that emit light of a specific wavelength after excitation with light of a characteristic wavelength lower than Alternatively, the label may be inherently capable of emitting a signal. It does not have to be capable of emitting a signal, but can be conjugated to another compound that emits a signal. An example of this latter situation is a labeled avidin that does not itself emit a signal. Or a label such as biotin that is detectable when bound to a streptavidin molecule. Another example of this latter type of label is a ligand that specifically binds to a particular receptor. The elutably labeled receptor binds to a ligand-labeled unit-specific marker for visualization. It can be done.

[0072] Labels that can be used in accordance with the present invention include, but are not limited to, electronic sensors. Pin resonance molecules, fluorescent molecules, chemiluminescent molecules, radioisotopes, enzyme substrates, enzymes, biotin molecules , avidin molecules, charge transfer molecules, semiconductor nanocrystals, semiconductor nanoparticles, colloidal gold nanocrystals , ligands, microbeads, magnetic beads, paramagnetic molecules, quantum dots, chromogenic substrates, affinity Molecules, proteins, peptides, nucleic acids, carbohydrates, haptens, antigens, antibodies, antibody fragments and lipids Quality is one of the key factors.

[0073] Radioisotopes can be detected by film or a charge-coupled device (CCD) and The enzyme can be detected by binding of a fluorescent, chemiluminescent, or enzyme-tagged receptor, The microbeads can be detected using electron or atomic force microscopy.

[0074] Conjugation of the label to the peptide follows routine protocols well known to those skilled in the art. This can be done.

[0075] In another embodiment, the peptide of the first aspect of the invention is optionally as provided above or below. In one embodiment, the compound is conjugated to a drug in combination with any of the embodiments described above. In this method, the drug is conjugated to the N-terminus of the peptide.

[0076] In another embodiment of the first aspect of the invention, optionally in the embodiments provided above or below In combination with any of the above, the peptide is conjugated to a cell membrane-penetrating peptide. .

[0077] In the present invention, the term "cell membrane penetrating peptide" ("CPP") refers to various molecular Cellular uptake of drugs (ranging from nano-sized particles to small chemical molecules and large DNA fragments) "Cargo" refers to a short peptide that is attached to the target molecule via a covalent chemical bond or non-covalently. It is associated with the peptide at C(t) or N(t) through covalent interactions. Their function is to deliver cargo into cells, which is generally achieved by endocytosis. The current use of CPPs is due to the lack of cell specificity in CPP-mediated cargo delivery. and limited by a poor understanding of their uptake modes. They contain relatively high relative amounts of positively charged amino acids such as arginine or arginine, or they have polar / either have a sequence containing an alternating pattern of charged and nonpolar, hydrophobic amino acids These two types of structures have the amino acid composition of polycationic A third class of CPPs is called amphipathic, which contains only nonpolar residues with a low net charge. or a hydrophobic peptide containing a hydrophobic amino acid group important for cellular uptake. Conjugation of CPPs to the peptides provided by the present invention can be achieved by solid-phase synthesis or solution synthesis. This can be done according to well-known routine protocols such as selective capping ( Copolovici DMet al.,“Cell-Penetrating Peptides: Design, Synthesis, and Application ns”,2014,ACS Nano,2014,8(3),pp1972-1994 In another embodiment of the first aspect of the invention, the method of claim 1 further comprises the steps of: In combination with any of the provided embodiments, the cell membrane penetrating peptide may be a polycationic CPP, polyArg or penetratin.

[0078] The method for preparing a peptide according to the first aspect of the present invention comprises: (1.a) The corresponding amino acids of the peptide, designated "i" and "i+4" or "i+7" by condensation of the compound of formula (III) and the compound of formula (IV) corresponding to the amino acid Compounds (III) and (IV) are coupled to form the "L" biradical. which undergoes a subsequent cyclization step: [ka] (In the formula, R 19 is as defined above, and Z1 and Z2 are the same or different. (C2-C 10 ) representing alkenyl); and (1.b) Z1 and Z2 carried out in solution using Grubbs catalyst (formation of I or II) A cyclization step involving ring-closing metathesis of Z2 (Kim Young-Woo et al., “ Synthesis of all-hydrocarbon stapled ah elical peptides by ring-closing olefin m etathesis”, Nature Protocols, 2011, 6(6), p. 761-771;Scott JMet al., “Application of Ring-Closing Metathesis to the Synthesis s of Rigidified Amino Acids and Peptides ”,J.Am.Chem.Soc.,1996,v.118(40),pp 9606- 9614); or (2a) the amino acids of formula (V Coupling by condensation of the compound of formula (VI) and the required amino acid containing compound of formula (VI). Compounds (V) and (VI) undergo a subsequent cyclization step to generate the "L" biradical. Becoming: [ka] [In the formula, R 19 is as defined above, and Z3 and Z4 are the same or different. Halogen -SH, -NHR 20 , -OH, (C2-C 10 ) alkyl-SH, (C1 -C 10 ) alkyl-OH, (C1-C 10 )Alkyl-NHR 21 , C(=O)OH, (C1-C 10 )C(=O)OH, C(=O)NHR 22 , (C1-C 10 ) Alkyl C (=O)NHR 23 , OR 24 , C(=O)-halogen, C(=O)-OR 25 , S(= O)-halogen, S(=O)-OR 26 , S(=O)2R 27 (In the formula, R20 , R 21 R 22 , R 23、 R 24 , R 25 R 26 and R 27 is hydrogen, (C1-C 10 )Archi le, (C2-C 10 ) alkenyl, and (C2-C 10 ) Alkynyl; 3 to 14 carbons A ring system containing 1 to 3 rings, each of which may be saturated, partially unsaturated, or a mixture of these rings. It is unified or aromatic; the rings may be isolated, partially or fully fused; The members forming the known ring systems are -CH-, -CH2-, -NH-, -N-, -S selected from the group consisting of -H-, -S-, and -O-; and The ring system may optionally be substituted with halogen, -OH, -NH, -SH, C(=O)-halogen ( C1-C 10 ) haloalkyl, and (C1-C 10 ) alkyl-O- and substituted with one or more groups selected from the group consisting of radical]; and (2b) a cyclization step comprising a coupling reaction between the Z3 and Z4 groups; or (3a) The corresponding amino acids of the peptide are designated "i" and "i+4" or "i+7". by condensation with a compound of formula (VII) and a compound of formula (VIII) corresponding to the amino acid to be A pairing. Compounds (VII) and (VIII) undergo subsequent cyclization to generate the "L" biradical. To be subjected to the process: [ka] (In the formula, R19 is as defined above, and one of Z5 and Z6 is (C2-C 10 ) alkynyl, and the other is (C-C 10 ) alkylN3); and (3.b) Well-known protocols, e.g., to generate 1,4-substituted 1,2,3 triazole bridges Cu(I)-mediated Huisgen 1,3-dipolar cycloaddition (also known as "Cl") Kolb HC et al., "The growing impulse act of click chemistry on drug discovery ”,2003,Drug Discov Today,8(24):1128-1137 A cyclization step comprising condensation of the Z5 and Z6 groups with the aryl group Z5.

[0079] The method for preparing a peptide according to the second aspect of the present invention comprises: Coupling of the C-terminus with the amino group or N-terminus of another amino acid by condensation, The coupling reaction is repeated as many times as necessary to obtain the desired peptide.

[0080] Compounds of formula (III), (IV), (V), (VI), (VII) and (VIII) It is commercially available and is coupled to an already formed portion of the peptide sequence by condensation. These compounds are suitable for the solid phase synthesis of peptides, as well as for the synthesis of carboxyl, acetyl, and hydroxybenzoates. Illustrative, non-limiting examples of compounds include: Specifically, 2-(2'-propenyl)alanine, 2-(3'-butenyl)glycine, 2-(4 '-pentenyl)alanine, 2-(6'-heptenyl)alanine, 2-(7'-octenyl)alanine (I) alanine, allyl-glycine, 5-azido-norvaline, and alpha-propargylic acid It is luceranine.

[0081] The "coupling" step was carried out according to the protocol "deprotection-wash-coupling-wash". , the amino acids defined above and alpha-alpha-disubstituted amino acids of formulae (II) to (VII) Using amino acids, the carboxyl group of one amino acid and the amino group of another amino acid residue are bonded This can be carried out on the solid phase by condensing

[0082] The general principle of solid-phase peptide synthesis is to repeat the cycle of deprotection-wash-coupling-wash. The free N-terminal amine of the solid-phase bound peptide is converted to a single N-protected amino acid unit. This unit is then deprotected to reveal a new unit to which a further amino acid can be attached. Amino acids have reactive moieties at the N- and C-termini, revealing a large N-terminal amine. These facilitate amino acid coupling during synthesis. Many amino acids also contain reactive side chain functionalities. groups, which interact with free termini or other side groups during synthesis and peptide elongation. This can adversely affect yield and purity. To achieve this, specific amino acid functional groups are bound to the hydroxyl group, blocking or protecting the functional groups from non-specific reactions. These protecting groups are numerous in nature and include the following: They can be divided into three groups: N-terminal protecting groups, C-terminal protecting groups (mainly used in solution-phase synthesis), ), and side chain protecting groups.

[0083] To couple the peptide, the carboxyl group is usually activated. It is important to speed up the reaction. There are two main types of activating groups: carbodiimides and However, triazolol pentafluorophenyl esters (FDPP , PFPOH]) and BOP-Cl are useful for cyclization of peptides.

[0084] The purified individual amino acids are reacted with these protecting groups prior to synthesis and then used in peptide synthesis. are selectively removed during certain steps.

[0085] Exemplary resins that may be used in accordance with the present invention include, but are not limited to: Included are: (1) alkenyl resins (e.g., REM resins, vinyl sulfone polymer bonds) (2) amine-functionalized resins (e.g., amidine resins) , N-(4-benzyloxybenzyl)hydroxylamine polymer-bound, (amino Methyl) polystyrene, polymer-bound (R)-(+)-α-methylbenzylamine, 2 -Chlorotrityl Knorr resin, 2-N-Fmoc-amino-dibenzocyclohepta- 1,4-Diene polymer-bound resin, 4-[4-(1-Fmoc-aminoethyl)-2- Methoxy-5-nitrophenoxy]butylamidomethyl-polystyrene resin, 4-benzo Polymer-bound 4-carboxybenzenesulfonamide Polymer-bound, bis(tert-butoxycarbonyl)thiopseudourea polymer-bound Dimethylaminomethyl-polystyrene, Fmoc-3-amino-3-(2-nitrophenyl)- (phenyl)propionic acid polymer-bound, N-methylaminomethylated polystyrene, PA L resin, Sieber amide resin, tert-butyl N-(2-mercaptoethyl) carboxylate Bamate polymer-bound, triphenylchloromethane-4-carboxamide polymer (3) benzhydrylamine (BHA) resin (e.g., 2-chlorobenzhydrylamine) HMPB-benzhydrylamine polymer-bound, 4 -Methylbenzhydrol polymer-bound, benzhydryl chloride polymer-bound , benzhydrylamine polymer-bound; (4) Br-functionalized resins (e.g., 4-(benzhydrylamine) (Benzyloxy)benzyl bromide polymer-bound, 4-bromopolystyrene, brominated P POA resin, brominated Wang resin, bromoacetal polymer-bound, bromopolystyrene Len, HypoGel® 200 Br, Polystyrene A-Br for Peptide Synthesis , Selenium bromide polymer-bound, TentaGel HL-Br, TentaGel M B-Br, TentaGel S-Br); (5) chloromethyl resin (e.g., 5-[4 -(chloromethyl)phenyl]pentyl]styrene polymer-bound, 4-(benzyl) 4-Methoxybenzhydryl chloride polymer-bound, 4-Methoxybenzhydryl chloride polymer (6) CHO-functionalized resins (e.g., (4-formyl-3-methoxyphenol) (4-formyl-3-methoxyphenoxymethyl) polystyrene, (4-formyl-3-methoxyphenoxymethyl) polystyrene Benzyloxybenzaldehyde, 3-benzyloxybenzaldehyde polymer-bound, 4-benzyloxy-2 ,6-Dimethoxybenzaldehyde Polymer-bound, Formylpolystyrene, Hypo Gel® 200 CHO, Indole Resin, Polystyrene A-CH(OEt) 2, TentaGel HL-CH(OEt)2); (7) Cl-functionalized resins (e.g., Polymer-bound, (chloromethyl)polystyrene, Merrifield resin (8) CO₂H functionalized resins (e.g., carboxyethyl polystyrene, HypoG el® 200COOH, Polystyrene AM-COOH, TentaGel H L-COOH, TentaGel MB-COOH, TentaGel S-COOH) (9) Hypogel resin (e.g., HypoGel® 200FMP, Hypo Gel® 200PHB, HypoGel® 200 Trt-OH, HypoGel® 200HMB); (10) I-functionalized resins (e.g., 4-iodomethyl-2-methylpropional); Iodophenol polymer-bound, iodopolystyrene; Janda-Jels™ (JandaJel™ Rink Amide, JandaJel-NH2, JandaJ el-Cl, JandaJel-4-mercaptophenol, JandaJel-OH, JandaJel-1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, JandaJel-1,3,4,6,7,8-hexahydro-2H-pyrimido-[1,2 -a]pyrimidine, JandaJel-morpholine, JandaJel-polypyridine, JandaJel-triphenylphosphine, JandaJel-Wang); (11) MBHA Resin ((3[4'-(hydroxymethyl)phenoxy]propionate-4-methyl) Rubenzhydrylamine resin, 4-(hydroxymethyl)phenoxyacetic acid MBHA resin Polymer-bound, HMBA-4-methylbenzhydrylamine Polymer-bound, 4-methylbenzhydrylamine Benzhydrylamine Hydrochloride Polymer-bound Capacity (Amine )); (12) NH2-functionalized resins ((aminomethyl)polystyrene, (aminomethyl)poly Styrene, HypoGel® 200NH2, Polystyrene AM-NH2, Poly Styrene microspheres 2-aminoethylated, polystyrene microspheres 2-bromoethylated 2-Hydroxyethylated Polystyrene Microspheres, TentaGel H L-NH2, Tentagel M Br, Tentagel M NH2, Tenta gel M OH, TentaGel MB-NH2, entaGel S-NH2, T entaGel S-NH2); (13) OH functionalized resins (e.g., 4-hydroxymethyl Benzoic acid polymer-bound, hydroxymethyl resin, OH-functionalized Wang Resin ns); (14) Oxime resins (e.g., 4-chlorobenzophenone oxime polymers) Bound type, benzophenone oxime Polymer bound type, 4-methoxybenzophenone oxy (15) PEG resin (e.g., ethylene glycol polymer-bound); (16) Boc- / Blz peptide synthesis resin (e.g., Boc-Lys(Boc )-Lys[Boc-Lys(Boc)]-Cys(Acm)-b-Ala-O-PAM Resin, Boc-Lys(Fmoc)-Lys[Boc-Lys(Fmoc)]-bA la-O-Pam resin, Boc-Lys(Boc)-Lys[Boc-Lys(Boc) ]-Lys{Boc-Lys(Boc)-Lys[Boc-Lys(Boc)]}-b- Ala-O-PAM resin, Boc-Lys(Fmoc)-Lys[Boc-Lys(Fm oc)]-Lys[Boc-Lys(Fmoc)-Lys{Boc-Lys(Fmoc) ]}-b-Ala-O-PAM resin, Boc-Lys(Boc)-Lys[Boc-Ly s(Boc)]-Lys{Boc-Lys(Boc)-Lys[Boc-Lys(Boc )]}-Cys(Acm)-b-Ala-O-PAM resin, Preloaded PAM Resins; (17) Fmoc- / t-Bu peptide synthesis resins (e.g., Fmoc-Lys( Fmoc)-Lys[Fmoc-Lys(Fmoc)]-b-Ala-O-Wang resin , Fmoc-Lys(Fmoc)-Lys[Fmoc-Lys(Fmoc)]-Lys{ Fmoc-Lys(Fmoc)-Lys[Fmoc-Lys(Fmoc)]}-b-Al aO-Wang Resin, Preloaded TentaGel® S Tri tyl resin, Preloaded TentaGel® resin, Preloaded Preloaded Trityl Resin, Preloaded Wang Resin, Amino Alcohol Pre loaded Trityl resin; (19) thiol-functionalized resin (e.g., HypoG el® 200 S-Trt, Polystyrene AM-S-Trityl, Ten taGel HL-S-Trityl, TentaGel MB-S-Trityl, T entaGel SS-Trityl); and (20) Wang resin (e.g., Fm oc-Ala-Wang resin, Fmoc-Arg(Pbf)-Wang resin, Fmoc- Arg(Pmc)-Wang resin, Fmoc-Asn(Trt)-Wang resin, Fmo c-Asp(OtBu)-Wang resin, Fmoc-Cys(Acm)-Wang resin, Fmoc-Cys(StBu)-Wang resin, Fmoc-Cys(Trt)Wang tree Fat, Fmoc-Gln(Trt)-Wang resin, Fmoc-Glu(OtBu)-Wa ng resin, Fmoc-Gly-Wang resin, Fmoc-His(Trt)-Wang resin fat, Fmoc-Ile-Wang resin, Fmoc-Leu-Wang resin, Fmoc-L ys(Boc)-Wang resin, Fmoc-Met-Wang resin, Fmoc-D-Me t-Wang resin, Fmoc-Phe-Wang resin, Fmoc-Pro-Wang resin , Fmoc-Ser(tBu)-Wang resin, Fmoc-Ser(Trt)-Wang Resin, Fmoc-Thr(tBu)-Wang resin, Fmoc-Trp(Boc)Wan g resin, Fmoc-Trp-Wang resin, Fmoc-Tyr(tBu)-Wang resin , Fmoc-Val-Wang resin).

[0086] A "protecting group" (PG) is a group that, when attached to a reactive group in a molecule, masks, reduces, or neutralizes that reactivity. refers to the grouping of atoms to be prevented.

[0087] Suitable amino protecting groups include methyl carbamate, ethyl carbamate, mate, 9-fluorenylmethylcarbamate (Fmoc), 9-(2-sulfo)fluoro Fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate , 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetramethyl- tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxy Phenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethylcarbamate (Teoc), 2-phenyl Ethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethylcarbamate, 1,1-dimethyl- 2,2-Dibromoethylcarbamate (DB-t-BOC), 1,1-dimethyl-2,2 , 2-trichloroethylcarbamate (TCBOC), 1-methyl-1-(4-biphenyl) 1-(3,5-di-t-butylphenyl) ethylcarbamate (Bpoc), 1-(3,5-di-t-butylphenyl) -1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridinyl) 2-(N,N-dicyclohexyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamide ) Ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate Carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc) , 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Co c), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N- Hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzylcarbamate p-Methoxybenzylcarbamate (Cbz), p-Methoxybenzylcarbamate (Moz), p-Nitrobenzylcarbamate Nitobenzyl bamate, p-bromobenzyl carbamate, p-chlorobenzyl Dichlorobenzylcarbamate, 2,4-dichlorobenzylcarbamate, 4-methylsulfinylbenzylcarbamate Anthrylmethylcarbamate (Msz), 9-anthrylmethylcarbamate, diphenylmethyl Carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate mate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithia methyl carbamate (Dmoc), 4-methylthiophenylcarbamate (Mt pc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethy propylcarbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate ( Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acid p-(dihydroxyboryl)benzylcarbamate, 5 -Benzisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6-chloro Monylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5- Dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy 6-nitrobenzylcarbamate, phenyl(o-nitrophenyl)methylcarbamate ate, phenothiazinyl-(10)-carbonyl derivative, N'-p-toluenesulfonyl Aminocarbonyl derivatives, N'-phenylaminothiocarbonyl derivatives, t-amylcarbonyl Bamate, S-benzylthiocarbamate, p-cyanobenzylcarbamate, cyclobutane cyclohexyl carbamate, cyclopentyl carbamate, cyclo Propylmethylcarbamate, p-decyloxybenzylcarbamate, 2,2-dimethicone Carbonyl vinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl Carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate Carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate Bamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobol isonicotinyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p' (-Methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate , 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate Bamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethylcarbamate, 1- Methyl-1-(p-phenylazophenyl)ethylcarbamate, 1-methyl-1-phenyl 1-methyl-1-(4-pyridyl)ethyl carbamate, phenylethyl carbamate Nylcarbamate, p-(phenylazo)benzylcarbamate, 2,4,6 tri-t- Butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, 2,4,6 trimethylbenzyl carbamate, formamide, acetamide, chloroacetamide acetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide , 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzamide Benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrilo o-Nitrophenylacetamide, o-Nitrophenoxyacetamide, Acetoacetamide, ( N'-Dithiobenzyloxycarbonylamino)acetamide, 3-(p-hydroxybenzoyl)acetamide phenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2 -(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenone) (oxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, o-(benzoyloxymethyl)benzamide, 4,5-diphenyl-3-oxazoline -2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-di Phenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyl Disilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl- 1,3,5-Triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3 ,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-Methylamine, N-Allylamine, N-[2-trimethylsilyl]ethoxy]methyl Amine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4- Nitro-2-oxo-3-pyrrolin-3-yl)amine, quaternary ammonium salt, N-benzyl N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuber N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenyl] N-9-phenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamine (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethyl Benzylamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylamine Phenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N' ,N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, N- p-Nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylidene Amine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-chloro- Chlohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl )amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(penta Carbonylchromium (or tungsten)carbonylamine, N-copper chelate, N-zinc Chelates, N-nitroamines, N-nitrosamines, amine N-oxides, diphenylphosphite Sphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthio Phosphinamide (Ppt), Dialkylphosphoramidate, Dibenzylphosphoramidate Date, diphenylphosphoramidate, benzenesulfenamide, o-nitrobenzene Nps, 2,4-dinitrobenzenesulfenamide, pentacene 2-nitro-4-methoxybenzenesulfenamide, Triphenylmethylsulfenamide, 3-nitropyridine sulfenamide (Npys ), p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,- Trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxy Benzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfone Amide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide amide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethyl Methylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide amide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide amide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthalene) (Dimethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, triflate Fluoromethylsulfonamide, and phenacylsulfonamide.

[0088] Examples of suitably protected carboxylic acids include, but are not limited to, silyl-, alkyl-, Further included are -, alkenyl-, aryl- and arylalkyl-protected carboxylic acids. Examples of suitable silyl groups include trimethylsilyl, triethylsilyl, t-butylsilyl, and t-butyldiphenylsilyl, triisopropylsilyl, and the like. Examples of suitable alkyl groups include methyl, benzyl, p-methoxybenzyl, 3,4-diphenylmethyl, and the like. Methoxybenzyl, trityl, t-butyl, tetrahydropyran-2-yl Examples of suitable alkenyl groups include allyl. Examples of suitable aryl groups include Examples of suitable aryl groups include optionally substituted phenyl, biphenyl, or naphthyl. Examples of alkyl groups include optionally substituted benzyl (e.g., p-methoxybenzyl). benzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl benzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl), and 2 - and 4-picolyl.

[0089] In a second aspect, the present invention provides a pharmaceutical or cosmetic composition.

[0090] As used herein, the phrase "therapeutically effective amount" refers to an amount of a compound that, when administered, passes through the bloodstream and The compound is sufficient to prevent or alleviate to some extent one or more of the symptoms of the disease being treated. The specific dose of peptide to be administered in accordance with the present invention will, of course, the symptoms, including the compound to be administered, the route of administration, the particular condition to be treated, and similar considerations. In one embodiment of the second aspect of the present invention, The pharmaceutical composition is a parenteral composition. In another embodiment, the pharmaceutical composition is for oral administration. The expression "cosmetically effective amount" as applied in the context of the present invention (e.g., topical) into the skin tissue (e.g., without significantly reaching the bloodstream or Refers to the amount of compound that is retained (at the subcutaneous level) and therefore exerts a local effect within the skin structure The particular dose of peptide to be administered in accordance with the present invention will, of course, vary from case to case. In one embodiment of the present invention, the " A "cosmetically effective amount" is a dose that achieves a therapeutic effect when administered parenterally, particularly by intravenous route. Higher than, equal to, or less than the amount required to produce

[0091] The term "pharmaceutically acceptable" means a compound that meets the requirements of the pharmaceutical arts for preparing a composition for pharmaceutical use. It refers to an excipient or carrier suitable for use in

[0092] The term "cosmetically acceptable" as used interchangeably herein means, inter alia, Suitable for use in contact with human skin without undue toxicity, incompatibility, instability or allergic reaction. It refers to an excipient or carrier suitable for

[0093] The phrase "excipient and / or carrier" refers to an acceptable material, composition, or vehicle. Each ingredient must be pharmaceutically or cosmetically acceptable in the sense that it is compatible with the other ingredients of the composition. and must be tolerated without excessive toxicity, irritation, allergic reaction, immunogenicity or in humans and non-human animals without other problems or complications commensurate with a reasonable benefit / risk ratio. It must be suitable for use in contact with tissues or organs. Examples are solvents, dispersion media, diluents or other liquid vehicles, dispersing or suspending aids, surfactants These include additives, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, etc. or otherwise affect any other (one or more) of the pharmaceutical or cosmetic composition. The conventional excipient vehicle may interact in a harmful manner with the substance or its derivatives. Except where incompatible with the conductor, such use is contemplated to be within the scope of the present invention.

[0094] The formulation of the pharmaceutical and cosmetic compositions described herein is based on known methods in the fields of pharmacology and cosmetics. They can be prepared by any method known or hereafter developed. The preparation method involves mixing the active ingredient (peptide) with an excipient and / or one or more other auxiliary ingredients. Combination and then, if necessary and / or desired, dispersing the product into desired single or multiple dose units. The method includes forming and / or packaging the product into a package.

[0095] The pharmaceutical compositions of the present invention may be administered in bulk solid form, as a single unit dose, and / or as multiple single unit doses. As used herein, "unit" refers to a unit that can be prepared, packaged, and / or sold as a single unit dose. A "dose" is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.

[0096] The active ingredient (i.e., as defined in the preceding aspects and embodiments) in the pharmaceutical composition of the present invention The relative amounts of the compound (peptide to be formulated), pharmaceutically acceptable excipient, and / or any additional ingredients may be Depending on the identity, size, and / or condition of the subject being treated, further consideration may be given to the route by which the composition is administered. It changes depending on the road.

[0097] Acceptable excipients that may be used in the preparation of these compositions include, but are not limited to, However, inert diluents, dispersing agents and / or granulating agents, surfactants and / or emulsifiers, disintegrating agents, Such excipients may optionally include additives, preservatives, buffers, lubricants and / or oils. Cocoa butter and suppository preparations may optionally be included in the formulations of the present invention, at the discretion of the formulator. Excipients such as waxes, colorants, coating agents, sweeteners, flavors, and fragrances may be added to the composition. May be present.

[0098] Exemplary diluents include, but are not limited to, calcium carbonate, sodium carbonate , calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, Sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, maize Triethanolamine, sorbitol, inositol, sodium chloride, dry starch, corn starch Examples of suitable granulated sugar include granulated sugar, granulated sugar, and combinations thereof.

[0099] Exemplary granulating and / or dispersing agents include, but are not limited to, potato denat. Punch, cornstarch, tapioca starch, sodium starch glycolate, clay, almond Acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, Natural sponge, cation exchange resin, calcium carbonate, silicate, sodium carbonate, cross-linked poly Vinylpyrrolidone) (crospovidone), sodium carboxymethyl starch (starch) Sodium carboxymethylcellulose, cross-linked carboxymethylcellulose Sodium cellulose (croscarmellose), methylcellulose, pregelatinized starch (de Starch 1500), microcrystalline starch, water-insoluble starch, carboxymethyl cellulose Calcium, Magnesium Aluminum Silicate (Veegum), Sodium Lauryl Sulfate , quaternary ammonium compounds and combinations thereof.

[0100] Exemplary surfactants and / or emulsifiers include, but are not limited to, natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, Chondrux, cholesterol, xanthan, pectin, gelatin, eggs yellow, casein, wool fat, cholesterol, wax and lecithin), colloidal clay (e.g. For example, bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate) [Nesium]), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol) Cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene Glycol distearate, glyceryl monostearate and propylene glycol mono stearates, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene , polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose), sorbitan fatty acid esters {e.g., polyoxyethylene Diethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan Tween 60, Polyoxyethylene sorbitan monooleate Tween 80 ], Sorbitan Monopalmitate [Span 40], Sorbitan Monostearate [Sp an60], sorbitan tristearate [Span65], glyceryl monooleate , sorbitan monooleate [Span 80]), polyoxyethylene esters (e.g. , Polyoxyethylene monostearate [Myrj45], Polyoxyethylene hardened castor oil Palm Oil, Polyethoxylated Castor Oil, Polyoxymethylene Stearate, and Soluto l), sucrose fatty acid ester, polyethylene glycol fatty acid ester (e.g., C remophor), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether [Brij30]), poly(vinylpyrrolidone), diethylene glycol monohydrate Nolaurate, Triethanolamine, Sodium Oleate, Potassium Oleate, Ethyl Oleate, Oleic Acid, Ethyl Laurate, Sodium Lauryl Sulfate, Pluronic F68, Poloxamer 188, Cetrimonium Bromide, Cetylpyridinium Chloride, Bleu Chloride and / or combinations thereof. can be.

[0101] Exemplary binders include, but are not limited to, starch (e.g., corn starch). and starch paste); gelatin; sugars (e.g., sucrose, glucose, dextrose) sugar, dextrin, molasses, lactose, lactitol, mannitol); natural and synthetic sugars Acacia, sodium alginate, Irish moss extract, panwar gum (p anwar gum), ghatti gum, isapol shell mucilage, carboxymethyl cellulose cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl Hydroxypropyl cellulose, Hydroxypropyl methylcellulose, Microcrystalline cellulose, Acetate cellulose (Veegum, polyvinylpyrrolidone), magnesium aluminum silicate and and larch arabogalactan; algin Acid salts;Polyethylene oxide;Polyethylene glycol;Inorganic calcium salts;Silicate;Poly wax; water; alcohol; and combinations thereof.

[0102] Exemplary preservatives include antioxidants, chelating agents, antibacterial preservatives, antifungal preservatives, alcohols, and the like. Examples of antioxidants include: Non-limiting examples include alpha tocopherol, ascorbic acid, and ascorbic acid palmitate. Colby, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycol Cerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate Examples include thorium, sodium bisulfite, sodium metabisulfite, and sodium sulfite. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid, Acid Monohydrate, Edetate Disodium, Edetate Dipotassium, Edetic Acid, Fumaric Acid, Apple Examples include edetate trisodium, tartaric acid, phosphate, edetate sodium, tartaric acid, and edetate trisodium. Suitable antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzyl chloride, thionium, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, Chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol alcohol, ethyl alcohol, glycerin, hexetidine, imidourea, phenol, phenon xyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol Exemplary antifungal preservatives include, but are not limited to, thimerosal, thimerosal, and thimerosal. Butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid , hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, Exemplary alcohol preservatives include sodium propionate and sorbic acid. Examples of suitable solvents include, but are not limited to, ethanol, polyethylene glycol, phenol, phenol compounds, bisphenols, chlorobutanol, hydroxybenzoic acid, and phenyl Exemplary acidic preservatives include, but are not limited to, ethyl alcohol. , Vitamin A, Vitamin C, Vitamin E, β-carotene, citric acid, acetic acid, dehydroacetic acid Other preservatives include, but are not limited to, ascorbic acid, sorbic acid, and phytic acid. Although it does not contain tocopherol, tocopherol acetate, deteroxime mesylate ( deteroxime mesylate), cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, lauryl sulfur Sodium Lauryl Ether Sulfate (SLS), Sodium Lauryl Ether Sulfate (SLES), Sodium Bisulfite Sodium, Sodium Metabisulfite, Potassium Sulfite, Potassium Metabisulfite, Glyda nt Plus, Phenonip, Methylparaben, Germall115, Germ Examples include Aben II, Neolone, Kathon, and Euxyl. In embodiments, the preservative is an antioxidant. In certain embodiments, the preservative is a chelating agent. .

[0103] Exemplary buffers include, but are not limited to, citrate buffer, acetate buffer, Phosphate buffer solution, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate , calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconate Conconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate Pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, hydroxyl Calcium phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixture dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixture, sodium acetate Thorium, Sodium Bicarbonate, Sodium Chloride, Sodium Citrate, Sodium Lactate, Dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixture, thoron Methamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free Examples include water, isotonic saline, Ringer's solution, ethyl alcohol, and combinations thereof. .

[0104] Exemplary lubricants include, but are not limited to, magnesium stearate, stearyl stearate, Calcium phosphate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated Vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride leucine, magnesium lauryl sulfate, sodium lauryl sulfate and combinations thereof Examples include:

[0105] Exemplary oils include, but are not limited to, almond, apricot kernel, avocado, and celery. Gado, babassu, bergamot, black current seeds, Borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon Coconut, cod liver, coffee, corn, cottonseed, emu, Potash, evening primrose, fish, flaxseed, geraniol, gourd, grape seeds, hazelnuts , hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender -, lemon, lily of the valley, macadamia nuts, mallow, mango seeds, meadowfoam seeds , mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel , peanuts, poppy seeds, pumpkin seeds, rapeseed, rice bran, rosemary, safflower, bean Saskatchewan, sasquana, savory, sea buckthorn, sesame, shea butter Turmeric, Silicone, Soybean, Sunflower, Tea Tree, Thistle, Camellia, Vetiver, Kuru Exemplary oils include, but are not limited to, stearic acid, maltodextrin, sorbitan ... starch, sorbitan stearate, and wheat germ oil. Butyl phosphate, caprylic triglyceride, capric triglyceride, cyclomethicone , Diethyl Sebacate, Dimethicone 360, Isopropyl Myristate, Mineral Oil, Octyl Dodecanol, oleyl alcohol, silicone oil, and combinations thereof. do.

[0106] Liquid dosage forms for parenteral administration include, but are not limited to, pharmaceutically acceptable liposomal formulations. Some emulsions, microemulsions, solutions, suspensions, syrups and elixirs In addition to the active ingredient, the liquid dosage form may contain inactive ingredients commonly used in the art. Diluents such as water or other solvents, solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, propyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, Propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (especially , cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), Glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan Specific embodiments for parenteral administration include fatty acid esters of hydroxybenzoates, ... In some embodiments, the conjugates of the present invention may be polyethoxylated castor oil (e.g., CREMO PHOR™), alcohol, oil, modified oil, glycol, polysorbate, cyclodecane, The composition is mixed with a solubilizer such as a hydroxyl group, a polymer, and combinations thereof.

[0107] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can contain suitable dispersing or wetting agents and Sterile injectable preparations can be formulated according to known techniques using pharmaceutical and suspending agents. a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent; It may be a solution in a solvent such as 1,3-butanediol. Among the vehicles and solvents are water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. Alternatively, the preparation may be in the form of liposomes.

[0108] Injectable preparations may be sterilized by, for example, filtration through a bacterial-retaining filter or by sterilizing with water before use. or in the form of a sterile solid composition that can be dissolved or dispersed in other sterile injectable media. It can be sterilized by incorporating a sterilizing agent.

[0109] To prolong the effect of a drug, it is often used to increase the absorption of the drug from a subcutaneous or intramuscular injection. This is because the use of a liquid suspension of crystalline or amorphous material with poor water solubility The rate of absorption of a drug depends upon its rate of dissolution, which is in turn determined by crystalline size. Alternatively, delayed absorption of a parenterally administered drug form may depend on the amount and crystalline form of the drug. This is achieved by dissolving or suspending in an oily vehicle.

[0110] The peptides of the present invention may be microencapsulated with one or more excipients as described above. In one embodiment, the peptides of the present invention are formulated in liposomes. .

[0111] It will be appreciated that the peptides and pharmaceutical compositions of the present invention may be used in combination therapy. The particular combination of therapies (therapeutics or procedures) used in a regimen depends on the desired therapeutic agent and and / or the suitability of the procedure and the desired therapeutic effect to be achieved. Therapies that are used can achieve the desired effect with the same purpose (e.g., to detect tumors). Useful conjugates of the invention are administered simultaneously with another agent useful for detecting tumors. may be able to achieve a different effect (e.g., limit any adverse effects) It will be understood that

[0112] The pharmaceutical compositions of the present invention may be administered alone or in combination with one or more other therapeutic agents. By "in combination with," it is meant that these delivery methods are within the scope of the present invention. that the drugs must be administered simultaneously and / or formulated for delivery together It is not intended that the composition must be administered in combination with one or more other desired treatments. It can be administered simultaneously with, before, or after a drug or medical procedure. The agents will be administered at a dose and / or on a time schedule determined for that agent. Furthermore, the present invention improves their bioavailability and reduces and / or eliminates their metabolism. and combinations with agents that can alter their function, inhibit their excretion, and / or alter their distribution in the body. The present invention also encompasses delivery of a combined peptide or pharmaceutical composition.

[0113] The particular combination of therapies used in a combination regimen will depend on the type of therapeutic agent and / or procedure desired. The therapeutic agent used will take into consideration its suitability and / or the desired therapeutic effect to be achieved. Therapies can achieve the desired effect for the same disorders (e.g., peptides of the invention). may be administered simultaneously with another bioactive agent to treat the same disorder), and / or It will be appreciated that different effects may be achieved (e.g., control of any adverse effects). The bioactive agents utilized in this combination may be administered together in a single composition. It will further be appreciated that the two compounds may be administered separately, either individually or in different compositions.

[0114] The term "in combination with" also refers to the use of a peptide of the invention in combination with, inter alia, a therapeutic agent or It is either an agent for improving the peptide profile (e.g., bioavailability) and (by chemical-physical interaction) any of the above and below additional agents It includes the possibility of conjugation.

[0115] In one embodiment, the peptides of the present invention are administered in combination with one or more anti-cancer agents. Anticancer drugs include, for example, methotrexate, vincristine, adriamycin, cisplatin, Platin, non-sugar containing chloroethylnitrosourea, 5-fluorouracil, mitochondrial Mycin C, bleomycin, doxorubicin, dacarbazine, taxol, flagellin , Meglamin GLA, Valrubicin, Calmutine and Polyferposan, MMI270 , BAY12-9566, RAS farnesyltransferase inhibitor, farnesyl Transferase inhibitors, MMP, MTA / LY231514, LY264618 / Metexol, Gramorec, CI-994, TNP-470, Hycanthin / Topotecan , PKC412, Valspodar / PSC833, Novantrone / Mitroxantrone ( Mitroxantrone, Metaret / Suramin, Batimasta , E7070, BCH-4556, CS-682, 9-AC, AG3340, AG3 433, Incel / VX-710, VX-853, ZD0101, ISI 641, ODN698, TA2516 / Marmistat, BB2 516 / Marmistat, CDP845, D2163, PD18 3805, DX895 if, Lemonal DP2202, FK 31 7. Picibanil / OK-432, AD32 / Valrubicin, Metastron / strontium derivative, Temodal / temozolomide Temozolomide, Evacet / liposomal doxorubicin Yewtaxan / paclitaxel, Taxol / paclitaxel Xeload / capecitabine, fluthulon / doxifluridine, cyclosporin Pax (Cyclopax) / oral paclitaxel, oral taxoid, SPU-077 / Cisplatin, HMR1275 / Flavopiridol, CP-358(774) / EGF R, CP-609(754) / RAS oncogene inhibitor, BMS-182751 / oral white Gold, UFT (tegafur / uracil), ergamisole / levamisole, eniluracil / 776C85 / 5FU enhancer, Campto / Levamisole, Camptosa / Irinotecan Can, Tumodex / Ralitrexed, Istatin / Cladribine, Paxex / Paclitaxel, Doxil / Lithium Liposomal doxorubicin, Caelyx / Liposomal doxorubicin, Rudara / Fludarabine, Pharmarubicin / Epirubicin Deposite, ZD1839, LU79553 / Bis-naphthalimide, LU1037 93 / Dolastatin, Caetyx / Liposomal doxorubicin, Gem Zar / Gemcitabine, ZD0473 / Anormed, YM116, Iodine Seed, C DK4 and CDK2 inhibitors, PARP inhibitors, D4809 / dexfosamide (Dexif osamide), Ifes / Mesnex / Ifosua Mido, Vumon / Teniposide, Paraplatin / Carboplatin, Planitino Plantinol / cisplatin, Vepeside / etoposide ZD9331, Taxotere / Docetaxel, a prodrug of guanine arabinoside alkyl amines such as taxane analogs, nitrosoureas, melphelan, and cyclophosphamide Antioxidants, aminoglutethimide, asparaginase, busulfan, carboplatin, chlorhexidine glucan Mubucil, Cytarabine HCl, Dactinomycin, Daunorubicin HCl, Estramus sodium thiazolinone phosphate, etoposide (VP16-213), floxuridine, fluoro Uracil (5-FU), flutamide, hydroxyurea (hydroxycarbamide), ifos Famido, interferon alpha-2a, alpha-2b, leuprolide acetate (LH RH-releasing factor analogue), lomustine (CCNU), mechlorethamine HCl (nitrogen mustard), mercaptopurine, mesna, mitotane (op-DDD), mitoxa Intolone HCl, Octreotide, Plicamycin, Procarbazine HCl, Strep Zosyn, tamoxifen citrate, thioguanine, thiotepa, vinblastine sulfate, am Cyclamin (m-AMSA), azacitidine, erythropoietin, hexamethylmelamine ( HMM), interleukin 2, mitoguazone (methyl-GAG; methylglyoxal bis-guanylhydrazone; MGBG), pentostatin (2'-deoxycoformyl semustine (methyl-CCNU), teniposide (VM-26) or vindesine sulfate , signal transduction inhibitors (MEK, BRAF, AKT, her2, mTOR, and PI3K inhibitors, etc.).

[0116] As exemplified below, the peptide of the first aspect of the present invention inhibits the proliferation of malignant melanocytes. are useful in the therapeutic treatment of melanoma, particularly metastatic melanoma, by reducing In one embodiment, optionally in combination with any of the embodiments provided above or below. In addition, when the peptide or pharmaceutical composition is used for therapeutic purposes, it may be administered orally or non-administered. It is administered orally.

[0117] The present invention also relates to the regulation of melanogenesis, in particular to the reduction or increase of melanin production. Also provided are non-therapeutic uses of the peptides or cosmetic salts thereof. All embodiments provided above with respect to are also embodiments of this aspect. In some embodiments, the peptide It can reduce hyperpigmentation (by reducing the amount of melanin) or hypopigmentation (by reducing the amount of melanin). For use in the treatment of rheumatoid arthritis (by increasing the amount of rheumatoid arthritis) In another embodiment, optionally in combination with any of the embodiments provided above or below. In another embodiment, melanogenesis in the skin or hair, particularly in the skin, is modulated. optionally in combination with any of the embodiments provided above or below, In one embodiment, the method comprises the steps of: When the peptide or cosmetic composition is used for non-therapeutic / cosmetic purposes, in combination with It is administered topically.

[0118] The present invention also provides a cosmetic method for treating hyperpigmentation or hypopigmentation, comprising the steps of: A peptide or a cosmetic salt thereof as defined in the first aspect of the invention or a peptide or a cosmetic salt thereof as defined in the second aspect of the invention The cosmetic method includes applying a cosmetic composition defined as follows: All of the above-provided examples relating to peptides and cosmetic compositions are not intended to encompass methods of treatment. The embodiment is also an embodiment of this aspect. In one embodiment of the cosmetic method, optionally, or in combination with any of the embodiments provided below, the peptide or cosmetic composition In one embodiment of the cosmetic method, the composition is applied to the skin and / or hair, optionally comprising the steps of: In combination with any of the embodiments provided herein, the peptide or cosmetic composition may be applied to the skin. It is used.

[0119] The present invention also relates to a peptide or a salt thereof as defined in any of the embodiments provided above. and a pigment-forming composition, such as a topical cosmetic pigment-forming composition or a pharmaceutical pigment-forming composition, comprising: Provide.

[0120] The present invention also relates to a peptide or a salt thereof as defined in any of the embodiments provided above. and a depigmenting composition, such as a topical cosmetic or pharmaceutical depigmenting composition, comprising: .

[0121] Throughout the specification and claims, the word "comprises" and variations of that word are used to mean other It is not intended to exclude technical features, additives, ingredients or processes. The word "comprise" also encompasses the word "consist of." These features and advantages will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples are offered by way of illustration and not by way of limitation. Furthermore, the present invention is not intended to limit the scope of the invention to the specific preferred embodiments described herein. All possible combinations of preferred embodiments are covered. [Example]

[0122] 1. Materials and Methods:

[0123] General procedure for synthesis

[0124] Compound IDP-F

[0125] Materials were purchased as follows: Fmoc-protected α-amino acids (---); Rinkami de MBHA resin(Tianjin Nankai HECHENG S&T Co. ,Ltd);HBTU((2-(1H-benzotriazol-1-yl)-1,1,3, 3-tetramethyluronium hexafluorophosphate), GL Biochem); N-methylmorpholine (Sinopharm Chemical Reagent Co. ., Ltd.); succinic anhydride (Aladdin); acetonitrile (Xingke C chemical); ninhydrin (Sinopharm Chemical Reage nt Co., Ltd.); piperidine (Vertellus); dimethylformamide ,DMF(Zhejiang jiangshan chemical co.,Ltd ); Trifluoroacetic acid, TFA (Trifluoroacetic acid, Solvay), TIS (Thioaniline) Solvay

[0126] Briefly, Fmoc-benzyl esters were prepared on Rink amide MBHA resin as a support. Linear polypeptides were synthesized manually using SPPS (solid phase peptide synthesis) at the source.

[0127] The following protocol was used: 1. The Fmoc protecting group was removed using 20% ​​piperidine in DMF. 2. The resin was washed five times with DMF. 3. The subsequent Fmoc-protected amino acid was reacted with Fmoc-AA (3 equivalents), HBTU (3 equivalents) ), and N-methylmorpholine (6 equivalents) for 45 minutes. 4. The resin was washed five times with DMF. Coupling was confirmed by the ninhydrin test. . 5. Repeat from step 1. 6. The N-terminus was reacted with succinic anhydride (10 equivalents) and N-methylmorpholine (10 equivalents). The cap was formed by reacting the cap with the cap.

[0128] Cleavage of the peptide from the resin into solution F (95% TFA, 2.5% water, 2.5% TIS) The resulting mixture was deprotected by exposure to 1000 uL of HCl and lyophilized.

[0129] The lyophilized peptide was purified by reversed-phase HPLC using a C18 column (see details (See Compound Characterization for details.) Peptides were identified by LC-MS-ESI. All mass spectral data for all compounds are shown in Table 1 below.

[0130] Materials were purchased as follows: Fmoc-protected α-amino acids (olefin amino acids, Fm oc-[(S)-2-(4-pentenyl)alanine]OH, Fmoc-[(R)-2-(4 Fmoc-[(S)-2-(7-octenyl)alanine]OH, Fmoc-[(S)-2-(7-octenyl)alanine]O H, containing other than Fmoc-[(R)-2-(4-pentenyl)alanine]OH, 2-( 6-chloro-1-H-benzotriazol-1-yl)-1,1,3,3-tetramethyl Aminium hexafluorophosphate (TBTU), resin, dimethylformamide (D MF), N,N-diisopropylethylamine (DIEA), trifluoroacetic acid (TFA ), 1,2-dichloroethane (DCE), Grubbs Ru(IV) catalyst and piperidin The materials (including the amines) were purchased from different suppliers.

[0131] Briefly, linear polypeptides were synthesized using an automated synthesizer using Fmoc solid-phase peptide chemistry. As disclosed in the previous section, after removing the resin from the reaction vessel, Only the coupling with the amino acid was performed manually.

[0132] Cleavage of the linear peptide from the resin as described by Scott JM et al. After that, ring-closing metathesis was carried out in solution using the first generation Grubbs catalyst (Sc ott JMet al., “Application of Ring-Clos ing Metathesis to the Synthesis of Rigid ified Amino Acids and Peptides”,1996,EN m.Chem.Soc.,1996,118(40),pp 9606-9614).

[0133] The deprotected peptide was precipitated with methyl tert-butyl ether at 4°C and lyophilized. It was dry.

[0134] The lyophilized peptide was purified by reversed-phase HPLC using a C18 column (see details (See Compound Characterization for details.) Peptides were identified by LC-MS-ESI. All mass spectral data for all compounds are shown in Table 1 below.

[0135] HPLC conditions:

[0136] IDP-F05; compounds were analyzed by HPLC-RP (C-18 column; Pump A: 0.1% Pump B: HO containing 0.1% TFA; Pump B: acetonitrile containing 0.1% TFA) Purification was performed using a linear gradient (RT = 10.2) from 30% to 40% B at 0 min. Purity grade by LC 95.06%;

[0137] IDP-F13; compounds were analyzed by HPLC-RP (C-18 column; Pump A: 0.1% Pump B: HO containing 0.1% TFA; Pump B: acetonitrile containing 0.1% TFA) Purification was performed using a linear gradient (RT = 14.26) from 32% to 42% B at 0 min. Purity grade 97.5% by PLC;

[0138] IDP-F16; compounds were analyzed by HPLC-RP (C-18 column; Pump A: 0.1% Pump B: HO containing 0.1% TFA; Pump B: acetonitrile containing 0.1% TFA) Purification was performed using a linear gradient (RT = 7.30) from 35% to 45% B at 0 min. Purity grade 95.7% by LC;

[0139] IDP-F18; compounds were analyzed by HPLC-RP (C-18 column; Pump A: 0.1% Pump B: HO containing 0.1% TFA; Pump B: acetonitrile containing 0.1% TFA) Use a linear gradient (RT = 10.97–11.97) from 51% to 61% B at 0 min. Purified. Purity grade by HPLC: 95.6%;

[0140] IDP-F22; compounds were analyzed by HPLC-RP (C-18 column; Pump A: 0.1% Pump B: HO containing 0.1% TFA; Pump B: acetonitrile containing 0.1% TFA) A linear gradient (RT = 10.1–11.36) of 53%–63% B was used at 0 min. Manufactured by HPLC. Purity grade 97.06%;

[0141] IDP-F29; compounds were analyzed by HPLC-RP (C-18 column; Pump A: 0.1% Pump B: HO containing 0.1% TFA; Pump B: acetonitrile containing 0.1% TFA) Purification was performed using a linear gradient (RT = 8.91) from 30% to 40% B at 0 min. Purity grade by LC ≤ 50%;

[0142] IDP-F31; compounds were analyzed by HPLC-RP (C-18 column; Pump A: 0.1% Pump B: HO containing 0.1% TFA; Pump B: acetonitrile containing 0.1% TFA) Purification was performed using a linear gradient (RT = 10:65) from 38% to 48% B at 0 min. Purity grade 95.49% by PLC;

[0143] [Table 1]

[0144] The X biradical has the formula: [ka] represents the compound -(CH2)3-CH=CH-(CH2)3- or -(CH2)6-CH=CH-(CH 2) An L biradical corresponding to 3- links both X groups in each sequence.

[0145] Cell line:

[0146] SK-MEL-28, skin, human malignant melanoma, ATCC-HTB-72™. IGR-37, human melanoma originating from skin, metastatic sites: inguinal lymph node. IGR-39, human melanoma originating from skin, metastatic sites: inguinal lymph node. B16-F10, skin, mouse melanoma, ATCC-CRL-6475™. 501-MEL, skin, human malignant melanoma.

[0147] cell culture

[0148] Cell lines SK-MEL-28, IGR-37, IGR-39, B16-F10, 501- MEL and A-375 were cultured in 10% inactivated fetal bovine serum (FBS, Dutcher, F rance), penicillin (50 U / ml) and streptomycin sulfate (50 mg Dulbecco's modified Eagle's medium containing 1000 mg of ATP per 1000 mg of ATP per ml (Gibco BRL, Germany) (Invitrogen Life Technologies, Foster Ci The cells were cultured in a 37°C incubator in a lab at 25°C (University of California, CA). , adherent cells in DPBS (Dulbecco's Phosphate Buffered Saline, Sigma D1283) Then, the cells were rinsed three times with trypsin ([0.5 g / ml] / in DPBS solution at 37 °C. EDTA [0.2 g / ml] (Gibco-BRL, 15400054) for 5 minutes. After detachment, the cells were transferred to culture medium. Each assay was performed when viability was greater than 90%. I went to see it.

[0149] Viability assay

[0150] Cell lines SK-MEL-28, IGR-37, B16-F10, 501-MEL and A- 375 were seeded in 96-well plates at a density of 1,000 cells / well. 24 hours later The compound to be tested was added and the efficacy was calculated at a concentration of 10 μM by serial dilution. Controls are untreated cells. Each experiment was performed in triplicate.

[0151] The cells were incubated in a CO2 incubator at 37°C for 72 hours. Cell viability was measured colorimetrically using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-dithiothiazol-2-yl). MTT was measured by the phenyltetrazolium bromide assay. The medium was then discarded and DMSO was added to dissolve the formazan product. , 570 with a microplate reader (MULTISKAN, Labsystems) The absorbance at 100 nm was measured. The percentage of cell survival was calculated by the percentage of cells treated with a given compound. The absorbance value of the cells was calculated by dividing it by the absorbance of untreated cells.

[0152] statistics

[0153] Data analysis was performed and normalized to the value of the negative control, which was considered equal to 100%. The percentage of cell viability was calculated. Dose / response curves were plotted using a sigmoidal dose-response ( (variable slope) and EC 50 The values ​​were calculated as follows: Y=Bottom+(Top-Bottom) / (1+10^{[(LogEC50- X)*HillSlope]}, where X is the compound concentration (logarithmic scale) and Y is the response.

[0154] Calculations and graphs were performed using GraphPad Prism (Prism for Windows). 6) was used.

[0155] 2.Results

[0156] 2.1 Efficacy Results

[0157] Tables 2a, 2b and 2c show the antiproliferative activity in several melanoma cell lines at 10 uM. Provides sex. [Table 2]

[0158] All peptides of the present invention were found to be effective against the malignant phenotype of the melanoma cell lines tested. It exhibits significant anticancer activity against cancer.

[0159] 2.2 Measurement of melanin content in B16-F10 melanoma cells

[0160] 25cm of B16-F10 melanoma cells 2 Cells were seeded into culture flasks and incubated for 24 hours. Then, 0.1 μM α-MSH was added, and the cells were incubated at their respective IC50s. The mice were treated with the above peptides at doses lower than 100 mg / kg for a total of 48 hours of incubation. After washing twice with phosphate-buffered saline, the cells were dissolved in 1 mL of 1 N NaOH. A 100 μL aliquot of the solution was then transferred to a 96-well plate for measurement of melanin content. Place in a microplate reader and measure the absorbance at 450 nm. Anti-melanin activity was measured as the percentage of melanin relative to the melanin of untreated melanoma cells. As a positive control, kojic acid (KA) was added at different concentrations (0.1, 1 and 10 μM).

[0161] The results are summarized in Figure 1. As can be seen, the peptides of the present invention inhibited the melanogenesis pathway. Therefore, some peptides may be melanocyte activation indicators. While other peptides such as F22 and F29 dramatically reduced the amount of melanin, Even more noteworthy is that the peptides of the present invention have a significantly reduced In this regard, the fact that the α-glucan was more efficient in regulating melanocytes. When KA was used at a concentration of 1 uM, the decrease was greater than when the peptide F22 of the present invention was used at the same concentration. It was found that the reduction was substantially lower than that achieved when

[0162] Therefore, this data supports the effect of the peptides of the present invention on melanocyte activity. Not only do they compare favorably with other compounds available in the state of the art that are currently used for the same purpose, It has also been shown to be even more efficient than the

[0163] 2.3 Determination of depigmenting activity in zebrafish embryos.

[0164] During zebrafish development, pigmentation is initiated by the retinal pigment epithelium (RPE) at approximately 24 hpf. Compound F2 then progresses towards the dorsolateral skin where melanocytes are distributed. Biochemical melanin quantification performed on untreated embryos for comparison with embryos treated with 2. F22 was added at 1x The stock solution was dissolved in PBS. To obtain the antibody, F22 was serially diluted in E3 medium to obtain: 2.5 μM in a final volume of 1 ml. .

[0165] Melanin quantification assay

[0166] Fifty embryos per triplicate were collected and lysed in lysis buffer at 95°C for 30 min. The L solution was placed in a 96-well plate and the total melanin was measured at 490 nm using a spectrophotometer. The content was quantified. The results were compared with synthetic melanin. The average 490 nm readings corrected by the chromatogram were plotted against their concentrations (µg / mL). The standard curve was used to determine the melanin protein concentration of each unknown sample. It was decided that:

[0167] Image analysis:

[0168] Allows automatic aspiration, placement, and rotation of larvae under a microscope (Leica, DM6-B) Embryos were placed in the robotic microfluidic system VAST (Union Biometrica). Once the embryo is positioned under a right angle (dorsal view), an image is captured by the VAST on-board camera. One dorsal image was acquired per larva. Quantification was performed using the FIJI program. The RGB image was converted to 8-bit and the orientation of the larvae was determined. A binary mask was generated from the image. A fixed threshold was applied to identify the larvae. Specific regions of interest (ROIs) were selected depending on the orientation of the larvae. The ROI was created so that the eye was excluded from quantification. Next, segmentation within the ROI was performed. The areas that were stained were measured using the pixel analysis command. The level of pigmentation was measured in those areas. The image was provided as the sum of all pixels in the image area.

[0169] Results: Melanin quantification

[0170]

number

[0171] Both assays used revealed biochemical melanin content and were compared with the imaging study. It can be concluded that there is evidence of a depigmenting effect of 2.5 μM compound F22. .

[0172] Reference list Altschul et al., “Basic local alignment search tool”, 1990, J. Mol. Biol, v. 2 15, pages 403-410; Copolovici DM et al., “Cell-Penetrating Peptides: Design, Synthesis, and App lications”, 2014, ACS Nano, 2014, 8 (3), pp 1972-1994; Higgins et al., “CLUSTAL V: improved software for multiple sequence alignment” , 1992, CABIOS, 8(2), pages 189-191; Kim Young-Woo et al., “Synthesis of all-hydrocarbon stapled a-helical peptides by ring-closing olefin metathesis”, Nature Protocols, 2011, 6(6), p. 761-771; Kolb HC et al., “The growing impact of click chemistry on drug discovery”, 2 003, Drug Discov Today, 8(24):1128-1137); and Scott JM et al., “Application of Ring-Closing Metathesis to the Synthesis of Rigidified Amino Acids and Peptides”, 1996, J. Am. Chem. Soc., 1996, 118 (40), p p 9606-9614;

[0173] For completeness, various aspects of the present invention are presented in the following numbered sections. Section 1; A peptide selected from the following, or a pharmaceutically or cosmetically acceptable salt thereof: (a) an amino acid sequence having at least 85% identity with the individual sequences of SEQ ID NO: 1 or 2; It has the columns: (Trp) m -(Asn) n -Lys-Gly-Thr-Ile-Leu-Lys-A la-Ser-Val-Asp-Tyr-Ile-Arg-Lys-(Leu) p -(G ln) q( Sequence number 1) (Arg) mx -(Arg) nx -Arg-Arg-Phe-Asn-Ile-Asn -Asp-Arg-Ile-Lys-Glu-Leu-Gly-Thr-Leu-(Il e) px -(Pro) qx( Sequence number 2) (In the formula, "m", "n", "p", and "q" represent integers and are selected from 0 and 1; "m x "," "n x ", "p x " and "q x " represents an integer and is selected from 0 and 1; The C-terminus corresponds to -C(O)R4; The N-terminus corresponds to -NHR5; R4 is -OH and -NR 17 R 18 is a group selected from the group consisting of: R5 is -H, (C1-C 20 ) alkyl, and halogen, (C1-C 10 )Archi -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 , and -CO2 R 12 (C1-C 10 ) alkyl is a group selected from the group consisting of: R 17 and R 18 is -H and (C1-C 10 ) alkyl, and halogen, (C1- C 10 )Alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 、 and -CO2R 12 (C1-C 10 ) alkyl; The alpha carbon atom of the amino acid at position "i" in the peptide sequence and the alpha carbon atom of the amino acid at position "i+4" or is a linker of the following formula (I) which links to the alpha carbon atom of the amino acid located at the "i+7" position: It also contains the carbonyl radical "L", -[(R1) a -(R2)-(R3) b ] c -(I) [In the formula, "a" and "b" are the same or different and are 0 or 1; "c" consists of 1 to 10; R1 and R3 are (C1-C 10 ) alkyl; halogen, (C1-C 10 ) alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 , and -CO2R1 substituted with one or more groups selected from the group consisting of (C1-C 10 ) alkyl;( C2-C 10 ) alkenyl; halogen, (C1-C 10 ) Alkyl, -OR6, -NR7 R8, -SR9, -SOR 10 , -SO2R 11 , and -CO2R 12 Selected from the group consisting of (C2-C 10 ) alkenyl; (C2-C 10 )a alkynyl; and halogens (C1-C 10 )Alkyl, -OR6, -NR7R8, -S R9, -SOR 10 , -SO2R 11 , and -CO2R 12 1 selected from the group consisting of or substituted with multiple groups (C2-C 10 ) alkynyl; It is a biradical; R2 is -O-, C(=O), C(=O)NR 13 , C(=O)O, S(=O), S( =O)2, NR 14 , (C1-C 10 ) alkyl, (C2-C 10 ) alkenyl, (C2 -C 10 ) alkynyl, -NR 15 -NR 16 -, -N=N-, -SS-, and 3~1 Known ring systems containing 4 members and 1 to 3 rings wherein each of said rings is saturated, partially unsaturated, or aromatic; the rings are isolated, partially or fully fused; The members forming the known ring system are -CH-, -CH2-, -NH-, -N-, selected from the group consisting of -SH-, -S-, and -O-; and The ring system may optionally be substituted with halogen, —OH, —NO, (C-C 10 ) alkyl, ( C1-C 10 ) haloalkyl, and (C1-C 10 ) alkyl-O- a biradical selected from the group consisting of and R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13、 R 14、 R 15、 and R 16 is -H and (C1-C 10 ) alkyl, ;and The amino acids linked by the linker are of formula (II) [ka] {In the formula, R 19 is (C1-C 10 ) alkyl, (C2-C10 ) alkenyl, (C2-C 10 ) alkynyl, and known ring systems containing 3 to 14 members and 1 to 3 rings wherein each of said rings is saturated, partially unsaturated, or aromatic; the rings are isolated, partially or fully fused; The members forming the known ring system are -CH-, -CH2-, -NH-, -N-, -SH-, -S- and -O-) a peptide containing a radical {]; and (b) an amino acid sequence having at least 85% identity with the individual sequences of SEQ ID NO: 1 or 2; It consists of columns: (Trp) m -(Asn) n -Lys-Gly-Thr-Ile-Leu-Lys-A la-Ser-Val-Asp-Tyr-Ile-Arg-Lys-(Leu) p -(G ln) q( Sequence number 1) (Arg) mx -(Arg) nx -Arg-Arg-Phe-Asn-Ile-Asn -Asp-Arg-Ile-Lys-Glu-Leu-Gly-Thr-Leu-(Il e) px -(Pro) qx( Sequence number 2) (In the formula, "m", "n", "p", and "q" represent integers and are selected from 0 and 1; "m x "," "n x ", "p x " and "q x " represents an integer and is selected from 0 and 1; The C-terminus corresponds to -C(O)R4; The N-terminus corresponds to -NHR5; R4 is -OH and -NR 17 R18 is a group selected from the group consisting of: R5 is -H, (C1-C 20 ) alkyl, and halogen, (C1-C 10 )Archi -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 , and -CO2 R 12 (C1-C 10 ) alkyl is a group selected from the group consisting of: R 17 and R 18 is -H, (C1-C 10 ) alkyl, and halogen, (C1-C 10 )Alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11、 and -CO2R 12 (C1-C1 0) alkyl; However, peptides other than those consisting of the sequences of SEQ ID NO: 24, 25 or 26. Section 2; A peptide according to claim 1, which has 100% identity to the sequence of SEQ ID NO: 1 or 2. Do. Section 3; The linker biradical of formula (I) is located at position "i" in the peptide sequence of SEQ ID NO: 1 The alpha carbon atom of the amino acid is located at the "i+7" position in the peptide sequence of SEQ ID NO: 1. between the alpha carbon atoms of an amino acid or in the peptide sequence of SEQ ID NO: 2 the alpha carbon atom of the amino acid at position i+7 in the peptide sequence of SEQ ID NO: 2 between the alpha carbon atom of the amino acid at position 1 and the alpha carbon atom of the amino acid at position 2. peptide. Section 4; Item 10. The peptide of any one of the preceding clauses, wherein a=b=c=1. Section 5; R1 and R3 are (C1-C 10 ) alkyl; (C2-C 10 ) alkenyl; and (C 2-C 10 ) a biradical independently selected from the group consisting of alkynyl; R2 is (C1-C 10 ) alkyl; (C2-C 10 ) alkenyl; and (C2-C1 0) a biradical selected from the group consisting of alkynyl; R 19 However, (C1-C 10 ) alkyl; (C2-C 10 ) alkenyl; and (C2-C 10 ) alkynyl; The peptide according to claim 1. Section 6; R1, R3 and R 19 (C1-C 10 ) alkyl, and R2 is (C2-C 10 )a 4. The peptide of any one of the preceding clauses, wherein the amino acid is alkenyl. Section 7; The C-terminus corresponds to -C(O)OH or -C(O)NH2, and the N-terminus corresponds to -N The peptide of any one of the preceding clauses, corresponding to H2. Section 8; A peptide sequence having at least 85%, at least 90%, or at least 95% or 100% identical, "L", "R19", "m", "n", "p", "q", "mx", "nx", "px", and "qx" are defined in any of claims 1 to 7. The peptide of any one of the preceding clauses, Section 9; A nucleic acid sequence having at least 85% or less identical amino acid sequence to a sequence selected from the group consisting of SEQ ID NOs: 17 to 23 having amino acid sequences with at least 90%, at least 95% or 100% identity. 3. The peptide according to any one of the preceding paragraphs. Section 10; A therapeutically effective amount or a cosmetically effective amount of the peptide according to any one of items 1 to 9, A pharmaceutical composition or composition comprising the compound together with pharmaceutically or cosmetically acceptable excipients and / or carriers. Cosmetic composition. Section 11; For the control of melanogenesis, in particular for increasing or decreasing melanin production, Item 9. A compound according to any one of items 10 to 13, wherein the compound is a peptide or a cosmetic salt thereof. Non-therapeutic uses of cosmetic compositions. Section 12; 12. Non-therapeutic use according to paragraph 11 for the treatment of hyperpigmentation or hypopigmentation. Section 13; A peptide or a compound according to any one of items 1 to 9 for use as a pharmaceutical. 11. A pharmaceutical salt thereof or a pharmaceutical composition according to item 10. Section 14; For use in the treatment and / or prevention of cancer, particularly melanoma cancer, such as metastatic melanoma cancer 10. A peptide or a pharmaceutical salt thereof according to any one of items 1 to 9, 11. The pharmaceutical composition according to item 10. Section 15; Inhibiting melanocyte proliferation in diseases related to dysregulation of melanogenesis, especially cancer A peptide according to any one of items 1 to 9 for use in the treatment and / or prevention of a disease caused by 11. A pharmaceutical composition according to claim 10, wherein the compound is a medicament for treating rheumatoid arthritis, ... or a pharmaceutical salt thereof.

Claims

1. A peptide selected from the following, or a pharmaceutically or cosmetically acceptable salt thereof: (a) an amino acid sequence having at least 85% identity with each of the sequences of SEQ ID NO: 1 or 2; Has the columns: (Trp) ｍ -(Asn) ｎ -Lys-Gly-Thr-Ile-Leu-Lys-A la-Ser-Vul-Asp-Tyr-Il-Arg-Ly-(Ly) ｐ -(G ln) ｑ（ SEQ ID NO: 1) (Arg) ｍｘ -(Arg) ｎｘ t0.834597 t0.834597 t0.834597 t0.834597 -Asp-Arg-Ile-Lys-Glu-Leu-Gly-Thr-Leu-(Il e) ｐｘ - (Pro) ｑｘ（ SEQ ID NO: 2) (In the formula, "m", "n", "p", and "q" represent integers and are selected from 0 and 1; "m ｘ "," "n ｘ "," "p ｘ " and "q ｘ " represents an integer and is selected from 0 and 1; The C-terminus is -C(O)R ４ Corresponding to; The N-terminus is -NHR ５ Corresponding to; R ４ is —OH and —NR １７ R １８ is a group selected from the group consisting of: R ５ is -H, (C １ -C ２０ ) alkyl, and halogen, (C １ -C １０ ) Alki Ru, -OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １２ (C １ -C １０ ) alkyl is a group selected from the group consisting of: R １７ and R １８ is -H and (C １ -C １０ ) alkyl, and halogen, (C １ - C １０ ) alkyl, —OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ 、 and -CO ２ R １２ (C １ -C １０ ) alkyl; The alpha carbon atom of the amino acid at position "i" in the peptide sequence and the alpha carbon atom of the amino acid at position "i+4" or is a linker of the following formula (I) which connects to the alpha carbon atom of the amino acid located at the "i+7" position: further comprising an alkyl radical "L"; -[(R １ ) ａ -(R ２ )-(R ３ ) ｂ ] ｃ -(I) [In the formula, "a" and "b" are the same or different and are 0 or 1; "c" consists of 1 to 10; R １ and R ３ is (C １ -C １０ ) alkyl; halogen, (C １ -C １０ ) alkyl, -OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １ ２ (C １ -C １０ ) alkyl; （ C ２ -C １０ ) alkenyl; halogen, (C １ -C １０ ) alkyl, —OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １２ Selected from the group consisting of (C ２ -C １０ ) alkenyl; (C ２ -C １０ )a and halogen, (C １ -C １０ ) alkyl, —OR ６ , -NR ７ R ８ , -S R ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １２ 1 selected from the group consisting of or substituted with multiple groups (C ２ -C １０ ) alkynyl; is a biradical; R ２ は、-O-、C(=O)、C(==)P １３ ,C(=O)O,S(=O),S( =O) ２ , N.R. １４ , (C １ -C １０ ) alkyl, (C ２ -C １０ ) alkenyl, (C ２ -C １０ ) alkynyl, —NR １５ -NR １６ -, -N=N-, -S-S-, and 3 to 1 Known ring systems containing four members and one to three rings wherein each of said rings is saturated, partially unsaturated, or aromatic; the rings are isolated, partially or fully fused; The members forming the known ring system are -CH-, -CH ２ -, -NH-, -N-, selected from the group consisting of —SH—, —S—, and —O—; and The ring system may optionally be substituted with halogen, —OH, —NO ２ , (C １ -C １０ ) alkyl, ( C １ -C １０ ) haloalkyl, and (C １ -C １０ ) alkyl-O- and a biradical selected from the group consisting of: and R ６ 、R ７ 、R ８ 、R ９ 、R １０ 、R １１ 、R １２ 、R １３、 R １４、 R １５、 and R １６ is -H and (C １ -C １０ ) alkyl; ;and The amino acids linked by the linker are of formula (II) 【Chemical 1】 {During the ceremony, R １９ is (C １ -C １０ ) alkyl, (C ２ -C １０ ) alkenyl, (C ２ -C １０ ) alkynyl, and known ring systems containing 3 to 14 members and containing 1 to 3 rings wherein each of said rings is saturated, partially unsaturated, or aromatic; the rings are isolated, partially or fully fused; The members forming the known ring system are -CH-, -CH ２ -, -NH-, -N-, -SH-, -S-, and -O-) a peptide containing a substituted or unsubstituted aryl group; (b) an amino acid sequence having at least 85% identity with each of the sequences of SEQ ID NO: 1 or 2; It consists of a sequence: (Trp) ｍ -(Asn) ｎ -Lys-Gly-Thr-Ile-Leu-Lys-A la-Ser-Vul-Asp-Tyr-Il-Arg-Ly-(Ly) ｐ -(G ln) ｑ（ SEQ ID NO: 1) (Arg) ｍｘ -(Arg) ｎｘ t0.834597 t0.834597 t0.834597 t0.834597 -Asp-Arg-Ile-Lys-Glu-Leu-Gly-Thr-Leu-(Il e) ｐｘ - (Pro) ｑｘ（ SEQ ID NO: 2) (In the formula, "m", "n", "p", and "q" represent integers and are selected from 0 and 1; "m ｘ "," "n ｘ "," "p ｘ " and "q ｘ " represents an integer and is selected from 0 and 1; The C-terminus is -C(O)R ４ Corresponding to; The N-terminus is -NHR ５ Corresponding to; R ４ is —OH and —NR １７ R １８ is a group selected from the group consisting of: R ５ is -H, (C １ -C ２０ ) alkyl, and halogen, (C １ -C １０ ) Alki Ru, -OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １２ (C １ -C １０ ) alkyl is a group selected from the group consisting of: R １７ and R １８ is -H, (C １ -C １０ ) alkyl, and halogen, (C １ -C １０ ) alkyl, —OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１、 and -CO ２ R １２ (C １ -C １ ０ ) alkyl); However, a peptide other than the peptide consisting of the sequence of SEQ ID NO: 24, 25 or 26.

2. The peptide of claim 1 having 100% identity to the sequence of SEQ ID NO: 1 or 2. Chid.

3. The linker biradical of formula (I) is located at position "i" in the peptide sequence of SEQ ID NO:

1. The alpha carbon atom of the amino acid is located at position "i+7" in the peptide sequence of SEQ ID NO:

1. between the alpha carbon atom of an amino acid or "i" in the peptide sequence of SEQ ID NO:2 the alpha carbon atom of the amino acid at position "i+7" in the peptide sequence of SEQ ID NO:2 3. The amino acid according to claim 1, wherein the carbon atom of the amino acid is The peptide according to claim 1.

4. 4. A peptide according to any one of claims 1 to 3, wherein a = b = c = 1.

5. R １ and R ３ However, (C １ -C １０ ) alkyl; (C ２ -C １０ ) alkenyl; and (C ２ -C １０ ) alkynyl; R ２ However, (C １ -C １０ ) alkyl; (C ２ -C １０ ) alkenyl; and (C ２ -C １ ０ ) alkynyl; R １９ However, (C １ -C １０ ) alkyl; (C ２ -C １０ ) alkenyl; and (C ２ -C １０ ) alkynyl. The peptide according to any one of claims 1 to 4.

6. R １ , R ３ and R １９ But (C １ -C １０ ) alkyl, and R ２ But (C ２ -C １０ )a 6. The peptide of claim 1, wherein the amino acid is alkenyl.

7. The C-terminus is —C(O)OH or —C(O)NH ２ and the N-terminus corresponds to -N H ２ 7. The peptide according to any one of claims 1 to 6, which corresponds to:

8. At least 85%, at least 90%, at least 95% or 100% identity, "L", "R19", "m", "n", "p", "q", "mx", "nx", "px", and "qx" are defined in any one of claims 1 to 7. The peptide of any one of claims 1 to 7.

9. Identifies at least 85% of an amino acid sequence selected from the group consisting of SEQ ID NOs: 17-23 and having amino acids with at least 90%, at least 95% or 100% identity.

9. The peptide according to any one of claims 1 to 8.

10. conjugated to a label, a drug, a cell-penetrating peptide or a PROTAC; A peptide according to any one of claims 1 to 9.

11. a therapeutically or cosmetically effective amount of having an amino acid sequence that has at least 85% identity with the individual sequences of SEQ ID NO: 1 or 2. death: (Trp) ｍ -(Asn) ｎ -Lys-Gly-Thr-Ile-Leu-Lys-A la-Ser-Vul-Asp-Tyr-Il-Arg-Ly-(Ly) ｐ -(G ln) ｑ（ SEQ ID NO: 1) (Arg) ｍｘ -(Arg) ｎｘ t0.834597 t0.834597 t0.834597 t0.834597 -Asp-Arg-Ile-Lys-Glu-Leu-Gly-Thr-Leu-(Il e) ｐｘ - (Pro) ｑｘ（ SEQ ID NO: 2) (In the formula, "m", "n", "p", and "q" represent integers and are selected from 0 and 1; "m ｘ "," "n ｘ "," "p ｘ " and "q ｘ " represents an integer and is selected from 0 and 1; The C-terminus is -C(O)R ４ Corresponding to; The N-terminus is -NHR ５ Corresponding to; R ４ is —OH and —NR １７ R １８ is a group selected from the group consisting of: R ５ is -H, (C １ -C ２０ ) alkyl, and halogen, (C １ -C １０ ) Alki Ru, -OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １２ (C １ -C １０ ) alkyl is a group selected from the group consisting of: R １７ and R １８ is -H, (C １ -C １０ ) alkyl, and halogen, (C １ -C １０ ) alkyl, —OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１、 and -CO ２ R １２ (C １ -C １ ０ ) alkyl); and optionally, The alpha carbon atom of the amino acid at position "i" in the sequence and the alpha carbon atom of the amino acid at position "i+4" or "i+ a linker of the following formula (I) linking the alpha carbon atom of the amino acid located at the "7" position to the containing the radical "L" -[(R １ ) ａ -(R ２ )-(R ３ ) ｂ ] ｃ -(I) [In the formula, "a" and "b" are the same or different and are 0 or 1; "c" consists of 1 to 10; R １ and R ３ is (C １ -C １０ ) alkyl; halogen, (C １ -C １０ ) alkyl, -OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １ ２ (C １ -C １０ ) alkyl; （ C ２ -C １０ ) alkenyl; halogen, (C １ -C １０ ) alkyl, —OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １２ Selected from the group consisting of (C ２ -C １０ ) alkenyl; (C ２ -C １０ )a and halogen, (C １ -C １０ ) alkyl, —OR ６ , -NR ７ R ８ , -S R ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １２ 1 selected from the group consisting of or substituted with multiple groups (C ２ -C １０ ) alkynyl; is a biradical; R ２ は、-O-、C(=O)、C(==)P １３ ,C(=O)O,S(=O),S( =O) ２ , N.R. １４ , (C １ -C １０ ) alkyl, (C ２ -C １０ ) alkenyl, (C ２ -C １０ ) alkynyl, —NR １５ -NR １６ -, -N=N-, -S-S-, and 3 to 1 Known ring systems containing four members and one to three rings wherein each of said rings is saturated, partially unsaturated, or aromatic; the rings are isolated, partially or fully fused; The members forming the known ring system are -CH-, -CH ２ -, -NH-, -N-, selected from the group consisting of —SH—, —S—, and —O—; and The ring system may optionally be substituted with halogen, —OH, —NO ２ , (C １ -C １０ ) alkyl, ( C １ -C １０ ) haloalkyl, and (C １ -C １０ ) alkyl-O- and a biradical selected from the group consisting of: and R ６ 、R ７ 、R ８ 、R ９ 、R １０ 、R １１ 、R １２ 、R １３、 R １４、 R １５、 and R １６ is -H and (C １ -C １０ ) alkyl; ;and The amino acids connected by the linker are of formula (II) 【Chemistry 2】 {During the ceremony, R １９ is (C １ -C １０ ) alkyl, (C ２ -C １０ ) alkenyl, (C ２ -C １０ ) alkynyl, and known ring systems containing 3 to 14 members and containing 1 to 3 rings wherein each of said rings is saturated, partially unsaturated, or aromatic; the rings are isolated, partially or fully fused; The members forming the known ring system are -CH-, -CH ２ -, -NH-, -N-, -SH-, -S-, and -O-) a peptide or a pharmaceutically or cosmetically acceptable salt thereof, A pharmaceutical or cosmetic composition comprising the compound together with a pharmaceutically or cosmetically acceptable excipient and / or carrier. product composition.

12. The peptide, pharmaceutical or cosmetic salt thereof, is a compound according to any one of claims 1 to 10.

12. The pharmaceutical or cosmetic composition according to claim 11, wherein

13. 13. The pharmaceutical or cosmetic composition according to any one of claims 11 to 12, which is a topical composition. composition.

14. Compositions for use in modulating melanogenesis, particularly for decreasing or increasing melanin production having an amino acid sequence having at least 85% identity with each of the sequences in SEQ ID NO: 1 or 2: (Trp) ｍ -(Asn) ｎ -Lys-Gly-Thr-Ile-Leu-Lys-A la-Ser-Vul-Asp-Tyr-Il-Arg-Ly-(Ly) ｐ -(G ln) ｑ（ SEQ ID NO: 1) (Arg) ｍｘ -(Arg) ｎｘ t0.834597 t0.834597 t0.834597 t0.834597 -Asp-Arg-Ile-Lys-Glu-Leu-Gly-Thr-Leu-(Il e) ｐｘ - (Pro) ｑｘ（ SEQ ID NO: 2) (In the formula, "m", "n", "p", and "q" represent integers and are selected from 0 and 1; "m ｘ "," "n ｘ "," "p ｘ " and "q ｘ " represents an integer and is selected from 0 and 1; The C-terminus is -C(O)R ４ Corresponding to; The N-terminus is -NHR ５ Corresponding to; R ４ is —OH and —NR １７ R １８ is a group selected from the group consisting of: R ５ is -H, (C １ -C ２０ ) alkyl, and halogen, (C １ -C １０ ) Alki Ru, -OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １２ (C １ -C １０ ) alkyl is a group selected from the group consisting of: R １７ and R １８ is -H, (C １ -C １０ ) alkyl, and halogen, (C １ -C １０ ) alkyl, —OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１、 and -CO ２ R １２ (C １ -C １ ０ ) alkyl; Optionally, the alpha carbon atom of the amino acid located at position "i" in the peptide sequence and the alpha carbon atom of the amino acid at the "i+4" or "i+7" position, comprising a linker biradical "L" of formula (I): -[(R １ ) ａ -(R ２ )-(R ３ ) ｂ ] ｃ -(I) [In the formula, "a" and "b" are the same or different and are 0 or 1; "c" consists of 1 to 10; R １ and R ３ is (C １ -C １０ ) alkyl; halogen, (C １ -C １０ ) alkyl, -OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １ ２ (C １ -C １０ ) alkyl; （ C ２ -C １０ ) alkenyl; halogen, (C １ -C １０ ) alkyl, —OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １２ Selected from the group consisting of (C ２ -C １０ ) alkenyl; (C ２ -C １０ )a and halogen, (C １ -C １０ ) alkyl, —OR ６ , -NR ７ R ８ , -S R ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １２ 1 selected from the group consisting of or substituted with multiple groups (C ２ -C １０ ) alkynyl; is a biradical; R ２ は、-O-、C(=O)、C(==)P １３ ,C(=O)O,S(=O),S( =O) ２ , N.R. １４ , (C １ -C １０ ) alkyl, (C ２ -C １０ ) alkenyl, (C ２ -C １０ ) alkynyl, —NR １５ -NR １６ -, -N=N-, -S-S-, and 3 to 1 Known ring systems containing four members and one to three rings wherein each of said rings is saturated, partially unsaturated, or aromatic; the rings are isolated, partially or fully fused; The members forming the known ring system are -CH-, -CH ２ -, -NH-, -N-, selected from the group consisting of —SH—, —S—, and —O—; and The ring system may optionally be substituted with halogen, —OH, —NO ２ , (C １ -C １０ ) alkyl, ( C １ -C １０ ) haloalkyl, and (C １ -C １０ ) alkyl-O- and a biradical selected from the group consisting of: and R ６ 、R ７ 、R ８ 、R ９ 、R １０ 、R １１ 、R １２ 、R １３、 R １４、 R １５、 and R １６ is -H and (C １ -C １０ ) alkyl; ;and The amino acids connected by the linker are of formula (II) 【Chemistry 3】 {During the ceremony, R １９ is (C １ -C １０ ) alkyl, (C ２ -C １０ ) alkenyl, (C ２ -C １０ ) alkynyl, and known ring systems containing 3 to 14 members and containing 1 to 3 rings wherein each of said rings is saturated, partially unsaturated, or aromatic; the rings are isolated, partially or fully fused; The members forming the known ring system are -CH-, -CH ２ -, -NH-, -N-, -SH-, -S-, and -O-) a peptide or salt thereof containing the group 14. The composition of any one of claims 11 to 13.

15. The peptide or salt thereof is as defined in any one of claims 1 to 10.

15. A peptide for use according to claim 14,

16. 16. Any one of claims 14 to 15 for the treatment of hyperpigmentation or hypopigmentation. A peptide or composition for use as described in claim 1.

17. A compound having at least 85% identity with an individual sequence of SEQ ID NO: 1 or 2 for use as a pharmaceutical. and a sequence of amino acids having the same identity: (Trp) ｍ -(Asn) ｎ -Lys-Gly-Thr-Ile-Leu-Lys-A la-Ser-Vul-Asp-Tyr-Il-Arg-Ly-(Ly) ｐ -(G ln) ｑ（ SEQ ID NO: 1) (Arg) ｍｘ -(Arg) ｎｘ t0.834597 t0.834597 t0.834597 t0.834597 -Asp-Arg-Ile-Lys-Glu-Leu-Gly-Thr-Leu-(Il e) ｐｘ - (Pro) ｑｘ（ SEQ ID NO: 2) (In the formula, "m", "n", "p", and "q" represent integers and are selected from 0 and 1; "m ｘ "," "n ｘ "," "p ｘ " and "q ｘ " represents an integer and is selected from 0 and 1; The C-terminus is -C(O)R ４ Corresponding to; The N-terminus is -NHR ５ Corresponding to; R ４ is —OH and —NR １７ R １８ is a group selected from the group consisting of: R ５ is -H, (C １ -C ２０ ) alkyl, and halogen, (C １ -C １０ ) Alki Ru, -OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １２ (C １ -C １０ ) alkyl is a group selected from the group consisting of: R １７ and R １８ is -H, (C １ -C １０ ) alkyl, and halogen, (C １ -C １０ ) alkyl, —OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１、 and -CO ２ R １２ (C １ -C １ ０ ) alkyl; Optionally, the alpha carbon atom of the amino acid located at position "i" in the peptide sequence and the alpha carbon atom of the amino acid at the "i+4" or "i+7" position, comprising a linker biradical "L" of formula (I): -[(R １ ) ａ -(R ２ )-(R ３ ) ｂ ] ｃ -(I) [In the formula, "a" and "b" are the same or different and are 0 or 1; "c" consists of 1 to 10; R １ and R ３ is (C １ -C １０ ) alkyl; halogen, (C １ -C １０ ) alkyl, -OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １ ２ (C １ -C １０ ) alkyl; （ C ２ -C １０ ) alkenyl; halogen, (C １ -C １０ ) alkyl, —OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １２ Selected from the group consisting of (C ２ -C １０ ) alkenyl; (C ２ -C １０ )a and halogen, (C １ -C １０ ) alkyl, —OR ６ , -NR ７ R ８ , -S R ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １２ 1 selected from the group consisting of or substituted with multiple groups (C ２ -C １０ ) alkynyl; is a biradical; R ２ は、-O-、C(=O)、C(==)P １３ ,C(=O)O,S(=O),S( =O) ２ , N.R. １４ , (C １ -C １０ ) alkyl, (C ２ -C １０ ) alkenyl, (C ２ -C １０ ) alkynyl, —NR １５ -NR １６ -, -N=N-, -S-S-, and 3 to 1 Known ring systems containing four members and one to three rings wherein each of said rings is saturated, partially unsaturated, or aromatic; the rings are isolated, partially or fully fused; The members forming the known ring system are -CH-, -CH ２ -, -NH-, -N-, selected from the group consisting of —SH—, —S—, and —O—; and The ring system may optionally be substituted with halogen, —OH, —NO ２ , (C １ -C １０ ) alkyl, ( C １ -C １０ ) haloalkyl, and (C １ -C １０ ) alkyl-O- and a biradical selected from the group consisting of: and R ６ 、R ７ 、R ８ 、R ９ 、R １０ 、R １１ 、R １２ 、R １３、 R １４、 R １５、 and R １６ is -H and (C １ -C １０ ) alkyl; ;and The amino acids connected by the linker are of formula (II) 【Chemistry 4】 {During the ceremony, R １９ is (C １ -C １０ ) alkyl, (C ２ -C １０ ) alkenyl, (C ２ -C １０ ) alkynyl, and known ring systems containing 3 to 14 members and containing 1 to 3 rings wherein each of said rings is saturated, partially unsaturated, or aromatic; the rings are isolated, partially or fully fused; The members forming the known ring system are -CH-, -CH ２ -, -NH-, -N-, -SH-, -S-, and -O-) a peptide or pharmaceutical salt thereof comprising the formula (I) or (II) ... The pharmaceutical composition described in any one of claims 1 to 4.

18. Use according to claim 17, as defined in any one of claims 1 to 10. A peptide or a salt thereof for the purpose of

19. For use in the treatment and / or prevention of cancer, particularly melanoma cancer, such as metastatic melanoma cancer amino acids having at least 85% identity with the individual sequences of SEQ ID NO: 1 or 2 for It has the acid sequence: (Trp) ｍ -(Asn) ｎ -Lys-Gly-Thr-Ile-Leu-Lys-A la-Ser-Vul-Asp-Tyr-Il-Arg-Ly-(Ly) ｐ -(G ln) ｑ（ SEQ ID NO: 1) (Arg) ｍｘ -(Arg) ｎｘ t0.834597 t0.834597 t0.834597 t0.834597 -Asp-Arg-Ile-Lys-Glu-Leu-Gly-Thr-Leu-(Il e) ｐｘ - (Pro) ｑｘ（ SEQ ID NO: 2) (In the formula, "m", "n", "p", and "q" represent integers and are selected from 0 and 1; "m ｘ "," "n ｘ "," "p ｘ " and "q ｘ " represents an integer and is selected from 0 and 1; The C-terminus is -C(O)R ４ Corresponding to; The N-terminus is -NHR ５ Corresponding to; R ４ is —OH and —NR １７ R １８ is a group selected from the group consisting of: R ５ is -H, (C １ -C ２０ ) alkyl, and halogen, (C １ -C １０ ) Alki Ru, -OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １２ (C １ -C １０ ) alkyl is a group selected from the group consisting of: R １７ and R １８ is -H, (C １ -C １０ ) alkyl, and halogen, (C １ -C １０ ) alkyl, —OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１、 and -CO ２ R １２ (C １ -C １ ０ ) alkyl; Optionally, the alpha carbon atom of the amino acid located at position "i" in the peptide sequence and the alpha carbon atom of the amino acid at the "i+4" or "i+7" position, comprising a linker biradical "L" of formula (I): -[(R １ ) ａ -(R ２ )-(R ３ ) ｂ ] ｃ -(I) [In the formula, "a" and "b" are the same or different and are 0 or 1; "c" consists of 1 to 10; R １ and R ３ is (C １ -C １０ ) alkyl; halogen, (C １ -C １０ ) alkyl, -OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １ ２ (C １ -C １０ ) alkyl; （ C ２ -C １０ ) alkenyl; halogen, (C １ -C １０ ) alkyl, —OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １２ Selected from the group consisting of (C ２ -C １０ ) alkenyl; (C ２ -C １０ )a and halogen, (C １ -C １０ ) alkyl, —OR ６ , -NR ７ R ８ , -S R ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １２ 1 selected from the group consisting of or substituted with multiple groups (C ２ -C １０ ) alkynyl; is a biradical; R ２ は、-O-、C(=O)、C(==)P １３ ,C(=O)O,S(=O),S( =O) ２ , N.R. １４ , (C １ -C １０ ) alkyl, (C ２ -C １０ ) alkenyl, (C ２ -C １０ ) alkynyl, —NR １５ -NR １６ -, -N=N-, -S-S-, and 3 to 1 Known ring systems containing four members and one to three rings wherein each of said rings is saturated, partially unsaturated, or aromatic; the rings are isolated, partially or fully fused; The members forming the known ring system are -CH-, -CH ２ -, -NH-, -N-, selected from the group consisting of —SH—, —S—, and —O—; and The ring system may optionally be substituted with halogen, —OH, —NO ２ , (C １ -C １０ ) alkyl, ( C １ -C １０ ) haloalkyl, and (C １ -C １０ ) alkyl-O- and a biradical selected from the group consisting of: and R ６ 、R ７ 、R ８ 、R ９ 、R １０ 、R １１ 、R １２ 、R １３、 R １４、 R １５、 and R １６ is -H and (C １ -C １０ ) alkyl; ;and The amino acids connected by the linker are of formula (II) 【Chemistry 5】 {During the ceremony, R １９ is (C １ -C １０ ) alkyl, (C ２ -C １０ ) alkenyl, (C ２ -C １０ ) alkynyl, and known ring systems containing 3 to 14 members and containing 1 to 3 rings wherein each of said rings is saturated, partially unsaturated, or aromatic; the rings are isolated, partially or fully fused; The members forming the known ring system are -CH-, -CH ２ -, -NH-, -N-, -SH-, -S-, and -O-) a peptide or pharmaceutical salt thereof comprising the formula (I) or (II) ... The pharmaceutical composition described in any one of claims 1 to 4.

20. The peptide or salt thereof is as defined in any one of claims 1 to 10.

20. The peptide or pharmaceutical salt thereof for use according to claim 19.

21. Inhibiting melanocyte proliferation in diseases related to dysregulation of melanogenesis, especially cancer and at least one of the individual sequences of SEQ ID NO: 1 or 2 for use in the treatment and / or prophylaxis of It has an amino acid sequence with 85% identity: (Trp) ｍ -(Asn) ｎ -Lys-Gly-Thr-Ile-Leu-Lys-A la-Ser-Vul-Asp-Tyr-Il-Arg-Ly-(Ly) ｐ -(G ln) ｑ（ SEQ ID NO: 1) (Arg) ｍｘ -(Arg) ｎｘ t0.834597 t0.834597 t0.834597 t0.834597 -Asp-Arg-Ile-Lys-Glu-Leu-Gly-Thr-Leu-(Il e) ｐｘ - (Pro) ｑｘ（ SEQ ID NO: 2) (In the formula, "m", "n", "p", and "q" represent integers and are selected from 0 and 1; "m ｘ "," "n ｘ "," "p ｘ " and "q ｘ " represents an integer and is selected from 0 and 1; The C-terminus is -C(O)R ４ Corresponding to; The N-terminus is -NHR ５ Corresponding to; R ４ is —OH and —NR １７ R １８ is a group selected from the group consisting of: R ５ is -H, (C １ -C ２０ ) alkyl, and halogen, (C １ -C １０ ) Alki Ru, -OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １２ (C １ -C １０ ) alkyl is a group selected from the group consisting of: R １７ and R １８ is -H, (C １ -C １０ ) alkyl, and halogen, (C １ -C １０ ) alkyl, —OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１、 and -CO ２ R １２ (C １ -C １ ０ ) alkyl; Optionally, the alpha carbon atom of the amino acid located at position "i" in the peptide sequence and the alpha carbon atom of the amino acid at the "i+4" or "i+7" position, comprising a linker biradical "L" of formula (I): -[(R １ ) ａ -(R ２ )-(R ３ ) ｂ ] ｃ -(I) [In the formula, "a" and "b" are the same or different and are 0 or 1; "c" consists of 1 to 10; R １ and R ３ is (C １ -C １０ ) alkyl; halogen, (C １ -C １０ ) alkyl, -OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １ ２ (C １ -C １０ ) alkyl; （ C ２ -C １０ ) alkenyl; halogen, (C １ -C １０ ) alkyl, —OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １２ Selected from the group consisting of (C ２ -C １０ ) alkenyl; (C ２ -C １０ )a and halogen, (C １ -C １０ ) alkyl, —OR ６ , -NR ７ R ８ , -S R ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １２ 1 selected from the group consisting of or substituted with multiple groups (C ２ -C １０ ) alkynyl; is a biradical; R ２ は、-O-、C(=O)、C(==)P １３ ,C(=O)O,S(=O),S( =O) ２ , N.R. １４ , (C １ -C １０ ) alkyl, (C ２ -C １０ ) alkenyl, (C ２ -C １０ ) alkynyl, —NR １５ -NR １６ -, -N=N-, -S-S-, and 3 to 1 Known ring systems containing four members and one to three rings wherein each of said rings is saturated, partially unsaturated, or aromatic; the rings are isolated, partially or fully fused; The members forming the known ring system are -CH-, -CH ２ -, -NH-, -N-, selected from the group consisting of —SH—, —S—, and —O—; and The ring system may optionally be substituted with halogen, —OH, —NO ２ , (C １ -C １０ ) alkyl, ( C １ -C １０ ) haloalkyl, and (C １ -C １０ ) alkyl-O- and a biradical selected from the group consisting of: and R ６ 、R ７ 、R ８ 、R ９ 、R １０ 、R １１ 、R １２ 、R １３、 R １４、 R １５、 and R １６ is -H and (C １ -C １０ ) alkyl; ;and The amino acids connected by the linker are of formula (II) 【Chemistry 6】 {During the ceremony, R １９ is (C １ -C １０ ) alkyl, (C ２ -C １０ ) alkenyl, (C ２ -C １０ ) alkynyl, and known ring systems containing 3 to 14 members and containing 1 to 3 rings wherein each of said rings is saturated, partially unsaturated, or aromatic; the rings are isolated, partially or fully fused; The members forming the known ring system are -CH-, -CH ２ -, -NH-, -N-, -SH-, -S-, and -O-) a peptide or pharmaceutical salt thereof comprising the formula (I) or (II) ... The pharmaceutical composition described in any one of claims 1 to 4.

22. 22. The use according to claim 21, as defined in any one of claims 1 to 10. A peptide or a pharmaceutical salt thereof for use in the treatment of rheumatoid arthritis.

23. having an amino acid sequence that has at least 85% identity with the individual sequences of SEQ ID NO: 1 or 2. death: (Trp) ｍ -(Asn) ｎ -Lys-Gly-Thr-Ile-Leu-Lys-A la-Ser-Vul-Asp-Tyr-Il-Arg-Ly-(Ly) ｐ -(G ln) ｑ（ SEQ ID NO: 1) (Arg) ｍｘ -(Arg) ｎｘ t0.834597 t0.834597 t0.834597 t0.834597 -Asp-Arg-Ile-Lys-Glu-Leu-Gly-Thr-Leu-(Il e) ｐｘ - (Pro) ｑｘ（ SEQ ID NO: 2) (In the formula, "m", "n", "p", and "q" represent integers and are selected from 0 and 1; "m ｘ "," "n ｘ "," "p ｘ " and "q ｘ " represents an integer and is selected from 0 and 1; The C-terminus is -C(O)R ４ Corresponding to; The N-terminus is -NHR ５ Corresponding to; R ４ is —OH and —NR １７ R １８ is a group selected from the group consisting of: R ５ is -H, (C １ -C ２０ ) alkyl, and halogen, (C １ -C １０ ) Alki Ru, -OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １２ (C １ -C １０ ) alkyl is a group selected from the group consisting of: R １７ and R １８ is -H, (C １ -C １０ ) alkyl, and halogen, (C １ -C １０ ) alkyl, —OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１、 and -CO ２ R １２ (C １ -C １ ０ ) alkyl; Optionally, the alpha carbon atom of the amino acid located at position "i" in the peptide sequence and the alpha carbon atom of the amino acid at the "i+4" or "i+7" position, comprising a linker biradical "L" of formula (I): -[(R １ ) ａ -(R ２ )-(R ３ ) ｂ ] ｃ -(I) [In the formula, "a" and "b" are the same or different and are 0 or 1; "c" consists of 1 to 10; R １ and R ３ is (C １ -C １０ ) alkyl; halogen, (C １ -C １０ ) alkyl, -OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １ ２ (C １ -C １０ ) alkyl; （ C ２ -C １０ ) alkenyl; halogen, (C １ -C １０ ) alkyl, —OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １２ Selected from the group consisting of (C ２ -C １０ ) alkenyl; (C ２ -C １０ )a and halogen, (C １ -C １０ ) alkyl, —OR ６ , -NR ７ R ８ , -S R ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １２ 1 selected from the group consisting of or substituted with multiple groups (C ２ -C １０ ) alkynyl; is a biradical; R ２ は、-O-、C(=O)、C(==)P １３ ,C(=O)O,S(=O),S( =O) ２ , N.R. １４ , (C １ -C １０ ) alkyl, (C ２ -C １０ ) alkenyl, (C ２ -C １０ ) alkynyl, —NR １５ -NR １６ -, -N=N-, -S-S-, and 3 to 1 Known ring systems containing four members and one to three rings wherein each of said rings is saturated, partially unsaturated, or aromatic; the rings are isolated, partially or fully fused; The members forming the known ring system are -CH-, -CH ２ -, -NH-, -N-, selected from the group consisting of —SH—, —S—, and —O—; and The ring system may optionally be substituted with halogen, —OH, —NO ２ , (C １ -C １０ ) alkyl, ( C １ -C １０ ) haloalkyl, and (C １ -C １０ ) alkyl-O- and a biradical selected from the group consisting of: and R ６ 、R ７ 、R ８ 、R ９ 、R １０ 、R １１ 、R １２ 、R １３、 R １４、 R １５、 and R １６ is -H and (C １ -C １０ ) alkyl; ;and The amino acids connected by the linker are of formula (II) 【Chemistry 7】 {During the ceremony, R １９ is (C １ -C １０ ) alkyl, (C ２ -C １０ ) alkenyl, (C ２ -C １０ ) alkynyl, and known ring systems containing 3 to 14 members and containing 1 to 3 rings wherein each of said rings is saturated, partially unsaturated, or aromatic; the rings are isolated, partially or fully fused; The members forming the known ring system are -CH-, -CH ２ -, -NH-, -N-, -SH-, -S-, and -O-) a peptide comprising a hydroxyl group, and one or more cosmetically acceptable excipients.

24. having an amino acid sequence that has at least 85% identity with the individual sequences of SEQ ID NO: 1 or 2. death: (Trp) ｍ -(Asn) ｎ -Lys-Gly-Thr-Ile-Leu-Lys-A la-Ser-Vul-Asp-Tyr-Il-Arg-Ly-(Ly) ｐ -(G ln) ｑ（ SEQ ID NO: 1) (Arg) ｍｘ -(Arg) ｎｘ t0.834597 t0.834597 t0.834597 t0.834597 -Asp-Arg-Ile-Lys-Glu-Leu-Gly-Thr-Leu-(Il e) ｐｘ - (Pro) ｑｘ（ SEQ ID NO: 2) (In the formula, "m", "n", "p", and "q" represent integers and are selected from 0 and 1; "m ｘ "," "n ｘ "," "p ｘ " and "q ｘ " represents an integer and is selected from 0 and 1; The C-terminus is -C(O)R ４ Corresponding to; The N-terminus is -NHR ５ Corresponding to; R ４ is —OH and —NR １７ R １８ is a group selected from the group consisting of: R ５ is -H, (C １ -C ２０ ) alkyl, and halogen, (C １ -C １０ ) Alki Ru, -OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １２ (C １ -C １０ ) alkyl is a group selected from the group consisting of: R １７ and R １８ is -H and (C １ -C １０ ) alkyl, and halogen, (C １ - C １０ ) alkyl, —OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ 、 and -CO ２ R １２ (C １ -C １０ ) alkyl); and optionally, The alpha carbon atom of the amino acid at position "i" in the peptide sequence and the alpha carbon atom of the amino acid at position "i+4" or "i a linker of the following formula (I) connecting the alpha carbon atom of the amino acid located at the "+7" position to the containing the biradical "L" -[(R １ ) ａ -(R ２ )-(R ３ ) ｂ ] ｃ -(I) [In the formula, "a" and "b" are the same or different and are 0 or 1; "c" consists of 1 to 10; R １ and R ３ is (C １ -C １０ ) alkyl; halogen, (C １ -C １０ ) alkyl, -OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １ ２ (C １ -C １０ ) alkyl; （ C ２ -C １０ ) alkenyl; halogen, (C １ -C １０ ) alkyl, —OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １２ Selected from the group consisting of (C ２ -C １０ ) alkenyl; and (C ２ -C １ ０ ) alkynyl; and halogen, (C １ -C １０ ) alkyl, —OR ６ , -NR ７ R ８ , -SR ９ , -SOR １０ , -SO ２ R １１ , and -CO ２ R １２ Selected from the group consisting of (C ２ -C １０ ) alkynyl; is a selected biradical; R ２ は、-O-、C(=O)、C(==)P １３ ,C(=O)O,S(=O),S( =O) ２ , N.R. １４ , (C １ -C １０ ) alkyl, (C ２ -C １０ ) alkenyl, (C ２ -C １０ ) alkynyl, —NR １５ -NR １６ -, -N=N-, -S-S-, and 3 to 1 Known ring systems containing four members and one to three rings wherein each of said rings is saturated, partially unsaturated, or aromatic; the rings are isolated, partially or fully fused; The members forming the known ring system are -CH-, -CH ２ -, -NH-, -N-, selected from the group consisting of —SH—, —S—, and —O—; and The ring system may optionally be substituted with halogen, —OH, —NO ２ , (C １ -C １０ ) alkyl, ( C １ -C １０ ) haloalkyl, and (C １ -C １０ ) alkyl-O- and a biradical selected from the group consisting of: and R ６ 、R ７ 、R ８ 、R ９ 、R １０ 、R １１ 、R １２ 、R １３、 R １４、 R １５、 and R １６ is -H and (C １ -C １０ ) alkyl; ;and The amino acids connected by the linker are of formula (II) 【Chemistry 8】 {During the ceremony, R １９ is (C １ -C １０ ) alkyl, (C ２ -C １０ ) alkenyl, (C ２ -C １０ ) alkynyl, and known ring systems containing 3 to 14 members and containing 1 to 3 rings wherein each of said rings is saturated, partially unsaturated, or aromatic; the rings are isolated, partially or fully fused; The members forming the known ring system are -CH-, -CH ２ -, -NH-, -N-, -SH-, -S-, and -O-) a peptide containing a hydroxyl group, wherein the hydroxyl group is a hydroxyl group, and one or more cosmetically acceptable excipients. A pigment-forming composition comprising:

25. 25. The composition of any one of claims 23 to 24, which is a topical composition.

26. 2. The peptide as defined in any one of claims 1 to 10.

26. The composition of any one of claims 3 to 25.

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