Polypeptides for repairing skin or mucosal damage and uses thereof

Abstract

This invention relates to polypeptides for repairing skin or mucosal damage, which have significant effects in alleviating the pathological progression of acute and chronic gastrointestinal diseases, promoting the repair of skin or mucosal damage, and treating tumors; and the use of said polypeptides for repairing skin trauma or mucosal damage. Specifically, this invention relates to polypeptides capable of binding to the FGFR1 receptor, which exert their effects of inhibiting or promoting cell proliferation, angiogenesis, and collagen formation by blocking or activating FGF / FGFR1 signaling.

Description

Technical Field

[0001] This invention relates to polypeptides for repairing skin or mucosal damage, which have significant effects in alleviating the pathological progression of acute and chronic gastrointestinal diseases, promoting the repair of skin or mucosal damage, and treating tumors; and the use of said polypeptides for repairing skin trauma or mucosal damage. Specifically, this invention relates to polypeptides capable of binding to the FGFR1 receptor, which exert their effects of inhibiting or promoting cell proliferation, angiogenesis, and collagen formation by blocking or activating FGF / FGFR1 signaling. Background Technology

[0002] At least 19 members of the fibroblast growth factor (FGF) family have been identified, playing crucial roles in development, angiogenesis, and wound healing. Their functions are achieved through binding to fibroblast growth factor receptors (FGFRs), which, via signal transduction systems, activate corresponding genes. Fibroblast growth factor receptors are a class of transmembrane tyrosine kinase receptors, and four types have been identified (FGFR1, FGFR2, FGFR3, and FGFR4), each encoded by a separate gene. Their functions are similar, involving the regulation of cell proliferation, differentiation, migration, and some pathological processes. FGFRs are widely distributed on the surface of target cells, such as epithelial cells, fibroblasts, and vascular endothelial cells. Phenotypic alterations of FGFRs are associated with hereditary diseases and malignant transformation of cells.

[0003] Fibroblast growth factors (FGFs) initiate intracellular signal transduction by binding to receptors (FGFRs), regulating cell proliferation, differentiation, and migration. Activation of FGFRs plays an important role in angiogenesis, embryonic development, tumor growth, and wound repair.

[0004] Skin and / or mucous membrane injury is a common pathological feature of many diseases. Skin injury refers to damage to normal skin (tissue) caused by external traumatic factors such as surgery, external force, heat, electric current, chemicals, and low temperature, as well as internal factors such as local blood supply disorders. It is often accompanied by the disruption of skin integrity and the loss of a certain amount of normal tissue, while also impairing normal skin function. It is also called a wound or trauma. Currently, protein / peptide drugs such as basic fibroblast growth factor, epidermal growth factor, platelet-derived growth factor, granulocyte-macrophage colony-stimulating factor, and growth hormone have significant effects on wound repair, skin care, anti-wrinkle, and anti-aging. However, the long amino acid sequences of these protein / peptide drugs lead to high preparation costs and poor stability, thus limiting their application.

[0005] Chronic gastritis is a chronic inflammation of the gastric mucosa, a common and frequently occurring disease in gastroenterology. Clinically, chronic gastritis refers to chronic inflammation of the gastric mucosa (pathologically manifested as mononuclear cell and lymphocyte infiltration) and / or glandular atrophic lesions caused by various factors. Chronic gastritis is more common in middle-aged and elderly people. Its onset is related to age but not to gender. It has a slow onset and a protracted course, making it difficult to cure and challenging to treat.

[0006] FGF / FGFR1 signaling is essential for normal cell growth, but excessive FGF secretion or insufficient expression can lead to various diseases. Studies have found that breast cancer, glioma, and liver cancer cells all express high levels of FGFR1, and abnormal FGFR1-mediated signaling is closely related to fibrotic diseases such as pulmonary fibrosis and cirrhosis. Furthermore, under conditions of skin or mucous membrane injury, activation of FGF / FGFR1 signaling can promote cell and tissue repair. Currently, many challenges remain in the treatment of skin and mucous membrane diseases and tumors, requiring further research and solutions from scientists to discover more and better drugs with therapeutic potential.

[0007] Given that current treatments cannot meet clinical needs, there is still a need for peptides that can better treat skin and mucous membrane diseases and tumors, such as acute and chronic gastrointestinal diseases and skin or mucous membrane injuries. Summary of the Invention

[0008] Through extensive experiments and research, the inventors of this invention have discovered that the polypeptide of this invention can bind to the FGFR1 receptor and exert its effects of inhibiting or promoting cell proliferation, angiogenesis, and collagen formation by blocking or activating FGF / FGFR1 signal transduction. Therefore, the polypeptide of this invention has significant effects in alleviating the pathological development of acute and chronic gastrointestinal diseases, promoting the repair of skin or mucous membrane damage, and treating tumors.

[0009] In a first aspect, the present invention provides compounds of formula (I) or physiologically compatible salts thereof, wherein the compounds of formula (I) are as follows:

[0010] HX aa1 -X aa2 -X aa3 -X aa4 -X aa5 -X aa6 -X aa7 -X aa8 -X aa9 -X aa10 -X aa11 -X aa12 -X aa13 -X aa14 -X aa15 -X aa16 -X aa17-X aa18 -X aa19 -OH(I),

[0011] in

[0012] X aa1 For Pro, missing;

[0013] X aa2 For Ala, missing;

[0014] X aa3 For Ser, Ala, Thr, missing;

[0015] Xaa4 is Met, Met(O), Val, Ala, Leu, Ile, Thr, Glu, Arg or missing;

[0016] X aa5 For Gln, Ala, Glu, Pro, Lys, or missing;

[0017] X aa6 For Ala, Ser, Val, Asp, or missing;

[0018] X aa7 Ser, Ala, Thr, Pro, Val, or missing;

[0019] X aa8 Leu, Ala, Val, Tyr, or missing;

[0020] X aa9 For Glu, Gln, Ala, Leu, Asp or missing;

[0021] X aa10 For Ala, Ser, or missing;

[0022] X aa11 For Glu, Gln, Ala, Leu, Asp or missing;

[0023] X aa12 For Ala, Ser, or missing;

[0024] X aa13 For Lys, Ala, Arg, His, or missing;

[0025] X aa14 Gly, Ala, Pro or missing;

[0026] X aa15 For Lys, Arg, Ala, His, or missing;

[0027] X aa16 For Ala, Ser, or missing;

[0028] X aa17 For Glu, Gln, Asp, Asn, Ala, Lys or missing;

[0029] X aa18 For Asp, Glu, Leu, Ala, Gln or missing; and

[0030] X aa19 For Asp, Glu, or missing; and

[0031] The condition is X aa1 X aa2 X aa3 Xaa4, X aa5 X aa6 X aa7 X aa8 X aa9 X aa10 X aa11 X aa12 X aa13 X aa14 X aa15 X aa16 X aa17 X aa18 and X aa19 At least four of them are not missing.

[0032] In one implementation scheme, X aa1 and X aa2 All are missing.

[0033] In one implementation scheme, X aa3 Ser or missing, preferably Ser.

[0034] In one implementation scheme, X aa4 Met or Met(O) or missing, preferably Met or Met(O).

[0035] In one implementation scheme, X aa3 -X aa4 It is Ser-Met, Ser-Met(O), Ser-Val, Ser-Ala, Ser-Leu, Ser-Ile, Thr-Met or missing, preferably Ser-Met, Ser-Met(O) or missing, more preferably Ser-Met.

[0036] In one implementation scheme, X aa5 It can be Gln or missing, preferably Gln.

[0037] In one implementation scheme, X aa6 It can be either Ala or missing, with Ala being the preferred choice.

[0038] In one implementation scheme, X aa7 Ser or missing, preferably Ser.

[0039] In one implementation scheme, X aa8 The value is Leu or missing, with Leu being the preferred value.

[0040] In one implementation scheme, X aa5 -X aa6 -X aa7 -X aa8 The values ​​are Gln-Ala-Ser-Leu, Gln-Ala-Ser-Ala, Ala-Ala-Ser-Leu, Gln-Ala-Ala-Leu, Glu-Ala-Ser-Leu, Gln-Ala-Thr-Leu, Gln-Ala-Ser-Val, Ala-Ser-Thr-Leu, Pro-Val-Pro-Leu, Lys-Asp-Val-Tyr, or missing, with Gln-Ala-Ser-Leu being preferred.

[0041] In one implementation scheme, X aa9 It can be Glu or Gln.

[0042] In one implementation scheme, X aa10 For Ala.

[0043] In one implementation scheme, X aa11 For Glu, Gln, or Ala.

[0044] In one implementation scheme, X aa12 For Ala.

[0045] In one implementation scheme, X aa13 For Lys.

[0046] In one implementation scheme, X aa9 -X aa10 -X aa11 -X aa12 For Glu-Ala-Glu-Ala, Gln-Ala-Gln-Ala, Ala-Ala-Glu-Ala, Glu-Ala-Ala-Ala, Leu-Ala-Glu-Ala, Glu-Ala-Leu-Ala, G ln-Ala-Glu-Ala, Glu-Ala-Gln-Ala, Asp-Ala-Glu-Ala, Glu-Ala-Asp-Ala, Glu-Ser-Glu-Ala, Glu-Ala-Glu-Ser or missing.

[0047] In one implementation scheme, Xaa9 -X aa10 -X aa11 -X aa12 -X aa13 For Glu-Ala-Glu-Ala-Lys, Gln-Ala-Gln-Ala-Lys, Glu-Ala-Glu-Ala-Ala, Ala-Ala-Glu-Ala-Lys, Glu- Ala-Ala-Ala-Lys, Glu-Ala-Glu-Ala-Arg, Glu-Ala-Glu-Ala-His, Leu-Ala-Glu-Ala-Lys, Glu-Ala-Le u-Ala-Lys, Gln-Ala-Glu-Ala-Lys, Glu-Ala-Gln-Ala-Lys, Asp-Ala-Glu-Ala-Lys, Glu-Ala-Asp-Ala- Lys, Glu-Ser-Glu-Ala-Lys, Glu-Ala-Glu-Ser-Lys, Glu-Ala-Glu-Ala or deletion, preferably Glu-Ala-Glu-Ala-Lys.

[0048] In one implementation scheme, X aa14 For Gly.

[0049] In one implementation scheme, X aa15 For Lys.

[0050] In one implementation scheme, X aa14 -X aa15 It can be Gly-Lys, Gly-Arg, Gly-Ala, Gly-His, Ala-Lys, Pro-Lys or missing, preferably Gly-Lys.

[0051] In one implementation scheme, X aa16 For Ala.

[0052] In one implementation scheme, X aa17 For Glu.

[0053] In one implementation scheme, X aa16 -X aa17 It is Ala-Glu, Ala-Gln, Ala-Asp, Ala-Asn, Ala-Ala, Ala-Lys, Ser-Glu or missing.

[0054] In one implementation scheme, X aa18 -X aa19 The values ​​are Asp, Glu, Leu, Ala, Gln-Asp, Gln-Glu, or are missing.

[0055] In one embodiment, the compound is selected from:

[0056] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (compound 1);

[0057] Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (compound 2);

[0058] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys (compound 3);

[0059] Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys (compound 4);

[0060] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys (compound 5);

[0061] Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys (compound 6);

[0062] Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (compound 7);

[0063] Ser-Met-Gln-Ala-Ser-Leu (compound 8);

[0064] Gln-Ala-Ser-Leu (compound 9);

[0065] Gly-Lys-Ala-Glu (compound 10);

[0066] Ser-Met(O)-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (compound 11);

[0067] Ser-Val-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (compound 12);

[0068] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Gln (compound 13);

[0069] Ser-Met-Gln-Ala-Ser-Leu-Gln-Ala-Gln-Ala-Lys-Gly-Lys-Ala-Glu (compound 14);

[0070] Ser-Met-Gln-Ala-Ser-Ala-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu(compound 15);

[0071] Ser-Ala-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (compound 16);

[0072] Ser-Leu-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (compound 17);

[0073] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Ala-Gly-Lys-Ala-Glu(compound 18);

[0074] Ser-Met-Gln-Ala-Ser-Leu-Ala-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (compound 19);

[0075] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Ala-Ala-Lys-Gly-Lys-Ala-Glu (compound 20);

[0076] Ser-Met-Ala-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu(compound21);

[0077] Ser-Ile-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (compound 22);

[0078] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Asp (compound 23);

[0079] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Asn (Compound 24);

[0080] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Arg-Ala-Glu (Compound 25);

[0081] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Ala-Ala-Glu (Compound 26);

[0082] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Ala (Compound 27);

[0083] Ser-Met-Gln-Ala-Ala-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (Compound 28);

[0084] Ala-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (Compound 29);

[0085] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Arg-Gly-Lys-Ala-Glu (Compound 30);

[0086] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-His-Ala-Glu (Compound 31);

[0087] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-His-Gly-Lys-Ala-Glu (Compound 32);

[0088] Ser-Met-Gln-Ala-Ser-Leu-Leu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (Compound 33);

[0089] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Leu-Ala-Lys-Gly-Lys-Ala-Glu (Compound 34);

[0090] Ser-Met-Gln-Ala-Ser-Leu-Gln-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (Compound 35);

[0091] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Gln-Ala-Lys-Gly-Lys-Ala-Glu (Compound 36);

[0092] Ser-Met-Glu-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (Compound 37);

[0093] Ser-Met-Gln-Ala-Ser-Leu-Asp-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (Compound 38);

[0094] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Asp-Ala-Lys-Gly-Lys-Ala-Glu (Compound 39);

[0095] Thr-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (Compound 40);

[0096] Ser-Met-Gln-Ala-Thr-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (Compound 41);

[0097] Ser-Met-Gln-Ala-Ser-Val-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (Compound 42);

[0098] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ser-Glu-Ala-Lys-Gly-Lys-Ala-Glu (Compound 43);

[0099] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ser-Lys-Gly-Lys-Ala-Glu (Compound 44);

[0100] Glu-Ala-Glu-Ala (Compound 45);

[0101] Glu-Ala-Glu-Ala-Lys-Gly-Lys (Compound 46);

[0102] Thr-Ala-Ser-Thr-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (Compound 47);

[0103] Ser-Thr-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (Compound 48);

[0104] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Gln-Asp (Compound 49);

[0105] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Gln-Glu (Compound 50);

[0106] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu-Leu (Compound 51);

[0107] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu-Ala (Compound 52);

[0108] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Lys-Gln-Asp (Compound 53);

[0109] Ala-Glu-Pro-Val-Pro-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (Compound 54);

[0110] Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (Compound 55);

[0111] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Ala-Lys-Ala-Glu (Compound 56);

[0112] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Pro-Lys-Ala-Glu (compound 57);

[0113] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Lys-Gln-Glu (compound 58);

[0114] Arg-Lys-Asp-Val-Tyr-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (compound 59);

[0115] Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ser-Glu (compound 60); or

[0116] Glu-Ala-Glu-Ala-Ala-Gly-Lys-Ala-Glu (Compound 61).

[0117] In a second aspect, the present invention provides the following compounds or physiologically compatible salts thereof:

[0118] Phe-Asp-Ala-Leu-Lys-Gln-Gln-Phe-Gln-Ala-Phe-Gln-Leu-Glu (compound 62);

[0119] His-Cys-Leu-Ala-Gly-Leu-Lys-Lys-Asp-Leu-Glu-Asp-Leu-Glu (compound 63);

[0120] Glu-Ile-Asn-Gln-Leu-Glu-Leu-Ile-Lys-Gln-Ala-Ser-Ile (compound 64);

[0121] Ala-Ala-Arg-Leu-Ala-Asp-Glu-Leu-Arg-Ala-Glu (compound 65);

[0122] Glu-Thr-Leu-Gln-Arg-Lys-Asn-Lys-Glu (compound 66);

[0123] Val-Asp-Ala-Ala-Val-Leu-Glu-Lys-Leu-Glu (compound 67);

[0124] Ala-Ala-Val-Leu-Asp-Lys-Leu-Glu (compound 68);

[0125] Ala-Ala-Val-Leu-Glu-Lys-Leu-Glu (compound 69);

[0126] Lys-Phe-Tyr-Ser-Gln-Ser-Thr-Ala-Ser-Ser-Ser-Tyr-Ala-Tyr-Pro-Ser-His-Phe-Gly-Pro-Ala-Gly-Phe-Ser-Gly-Ser-His-Ser (compound 70);

[0127] Val-Asp-Ala-Ala-Val-Ile-Glu-Lys-Ile-Glu (compound 71);

[0128] Val-Asp-Ala-Ala-Met-Val-Leu-Leu-Thr-Arg (compound 72); or

[0129] Val-Asp-Ala-Ala-Val-Leu-Met-Leu-Arg-Thr (compound 73).

[0130] For convenience, the H on the left and the OH on the right are omitted when describing the compounds of the present invention in this application.

[0131] Thirdly, the present invention provides a method for repairing skin trauma, the method comprising contacting the skin trauma with a compound of the present invention (i.e., the compound of the first or second aspect above) or a physiologically compatible salt thereof; or, the present invention provides the use of a compound of the present invention (i.e., the compound of the first or second aspect above) or a physiologically compatible salt thereof in the preparation of a medicament or cosmetic for repairing skin trauma; or the present invention provides a compound of the present invention (i.e., the compound of the first or second aspect above) or a physiologically compatible salt thereof for repairing skin trauma. In one embodiment, the skin trauma is related to, but is not limited to, epidermal inflammation, mechanical and surgical wounds, burns and scalds, ulcers, fistulas, pressure sores, and skin damage caused by radiotherapy and chemotherapy. In one embodiment, the skin trauma refers to damage to normal skin caused by external injury factors such as surgery, external force, heat, electric current, chemicals, low temperature, and internal factors such as local blood supply disorders. In one embodiment, the skin trauma is often accompanied by disruption of skin integrity and loss of a certain amount of normal tissue. In another embodiment, the skin trauma includes impairment of normal skin function.

[0132] This invention provides a method for promoting HaCAT cell proliferation, the method comprising contacting the cells with a compound of the invention (i.e., the compound of the first or second aspect above) or a physiologically compatible salt thereof. Alternatively, this invention provides the use of a compound of the invention (i.e., the compound of the first or second aspect above) or a physiologically compatible salt thereof in the preparation of a medicament for promoting HaCAT cell proliferation; or this invention provides a compound of the invention (i.e., the compound of the first or second aspect above) or a physiologically compatible salt thereof for promoting HaCAT cell proliferation.

[0133] Fourthly, the present invention provides a method for repairing mucosal damage, the method comprising administering a compound of the present invention or a physiologically compatible salt thereof to a subject or contacting the mucosal damage with the compound of the present invention or a physiologically compatible salt thereof. Alternatively, the present invention provides the use of the compound of the present invention (i.e., the compound of the first or second aspect above) or a physiologically compatible salt thereof in the preparation of a medicament for repairing mucosal damage; or the present invention provides the compound of the present invention (i.e., the compound of the first or second aspect above) or a physiologically compatible salt thereof for repairing mucosal damage.

[0134] In one embodiment, the mucosal injury is mucosal injury within cavities such as the digestive or respiratory systems.

[0135] Mucosal damage to the digestive system is associated with oral, esophageal, and gastrointestinal diseases. Oral diseases include oral ulcers, stomatitis, gingivitis, periodontitis, etc.; esophageal diseases include esophagitis, esophageal ulcers, etc.; and gastrointestinal diseases include, but are not limited to, mucosal damage caused by radiotherapy and chemotherapy, such as chronic gastritis, chronic atrophic gastritis, acute gastritis, gastroduodenal ulcers, functional gastrointestinal disorders, dyspepsia, precancerous lesions, digestive system tumors, gastrointestinal bleeding, gastroesophageal reflux disease, acute and chronic enteritis, ulcerative colitis, Crohn's disease, and radiotherapy and chemotherapy.

[0136] In a preferred embodiment, the digestive tract mucosa includes the gastric mucosa and the intestinal mucosa. In a preferred embodiment, the mucosal injury is gastric mucosal injury caused by irritants or drugs, or stress. Irritants include hydrochloric acid, ethanol, or alcohol, and drugs include nonsteroidal anti-inflammatory drugs such as aspirin or indomethacin.

[0137] This invention provides a method for preventing, alleviating, or treating gastrointestinal diseases or eliminating inflammatory edema, the method comprising administering to a subject a compound of the invention or a physiologically compatible salt thereof. Alternatively, this invention provides the use of a compound of the invention (i.e., the compound of the first or second aspect above) or a physiologically compatible salt thereof in the preparation of a medicament for preventing, alleviating, or treating gastrointestinal diseases or eliminating inflammatory edema; or this invention provides a compound of the invention (i.e., the compound of the first or second aspect above) or a physiologically compatible salt thereof for preventing, alleviating, or treating gastrointestinal diseases or eliminating inflammatory edema. The digestive tract diseases mentioned include those related to the oral cavity, esophagus, and gastrointestinal tract. Oral diseases include oral ulcers, stomatitis, gingivitis, periodontitis, etc.; esophageal diseases include esophagitis, esophageal ulcers, etc.; and gastrointestinal diseases include chronic gastritis, chronic atrophic gastritis, acute gastritis, gastroduodenal ulcers, functional gastrointestinal disorders, dyspepsia, precancerous lesions, digestive system tumors, gastrointestinal bleeding, gastroesophageal reflux disease, acute and chronic enteritis, ulcerative colitis, Crohn's disease, and mucosal damage caused by radiotherapy and chemotherapy; but are not limited thereto. In one embodiment, the prevention, mitigation, or treatment of the digestive tract diseases is achieved by regulating stem cell proliferation and differentiation. The method utilizes the compounds of the present invention or their physiologically compatible salts to protect or repair damage to the gastrointestinal mucosa, such as the gastric or intestinal mucosa, thereby preventing, mitigating, or treating gastrointestinal diseases.

[0138] This invention provides a method for repairing skin trauma or mucosal damage, the method comprising administering to a subject a compound of the invention (i.e., the compound of the first or second aspect above) or a physiologically compatible salt thereof. Alternatively, this invention provides the use of a compound of the invention (i.e., the compound of the first or second aspect above) or a physiologically compatible salt thereof in the preparation of a medicament or cosmetic for repairing skin trauma or mucosal damage; or this invention provides a compound of the invention (i.e., the compound of the first or second aspect above) or a physiologically compatible salt thereof for repairing skin trauma or mucosal damage.

[0139] This invention provides a method for blocking or activating FGF / FGFR1 signaling, the method comprising administering to a subject a compound of the invention (i.e., the compound of the first or second aspect above) or a physiologically compatible salt thereof, causing it to bind to an FGFR1 receptor, thereby blocking or activating FGF / FGFR1 signaling and exerting an inhibitory or promotion effect on cell proliferation, angiogenesis, and collagen formation. Alternatively, this invention provides the use of the compound of the invention (i.e., the compound of the first or second aspect above) or a physiologically compatible salt thereof in the preparation of a medicament for blocking or activating FGF / FGFR1 signaling; or this invention provides the compound of the invention (i.e., the compound of the first or second aspect above) or a physiologically compatible salt thereof, which is used to block or activate FGF / FGFR1 signaling. In a further embodiment, the compound of the invention (i.e., the compound of the first or second aspect above) binds to an FGFR1 receptor, thereby blocking or activating FGF / FGFR1 signaling and exerting an inhibitory or promotion effect on cell proliferation, angiogenesis, and collagen formation. In one embodiment, the present invention provides a method for activating FGF / FGFR1 signaling, the method comprising administering to a subject a compound of the present invention (i.e., the compound of the first or second aspect above) or a physiologically compatible salt thereof, causing it to bind to an FGFR1 receptor, thereby activating FGF / FGFR1 signaling and exerting an inhibitory or promoting effect on cell proliferation, angiogenesis, and collagen formation; or, the present invention provides a compound of the present invention (i.e., the compound of the first or second aspect above) or a physiologically compatible salt thereof for activating FGF / FGFR1 signaling; or the present invention provides the use of a compound of the present invention (i.e., the compound of the first or second aspect above) or a physiologically compatible salt thereof in the preparation of a medicament for activating FGF / FGFR1 signaling.

[0140] This invention provides a method for treating diseases related to FGFR targets, the method comprising administering to a subject a compound of the invention (i.e., the compound of the first or second aspect above) or a physiologically compatible salt thereof. Alternatively, this invention provides the use of a compound of the invention (i.e., the compound of the first or second aspect above) or a physiologically compatible salt thereof in the preparation of a medicament for treating diseases related to FGFR targets; or this invention provides a compound of the invention (i.e., the compound of the first or second aspect above) or a physiologically compatible salt thereof for treating diseases related to FGFR targets. In one embodiment, the FGFR target is FGFR1. In one embodiment, the disease related to the FGFR target is cancer or tumor.

[0141] In the methods of the present invention described above, the compounds of the present invention or their physiologically compatible salts are administered by oral, injection, subcutaneous, or other means.

[0142] Fifthly, the present invention provides a pharmaceutical, food, health product, cosmetic, or daily product composition, said composition comprising the compound of the present invention or a physiologically compatible salt thereof, and a physiologically acceptable carrier. In one embodiment, the physiologically acceptable carrier comprises a pharmaceutically acceptable carrier or a cosmetically acceptable carrier. The pharmaceutical, food, health product, cosmetic, or daily product composition can be prepared according to conventional pharmaceutical or cosmetic techniques, including mixing the compound of the present invention as an active ingredient with a carrier and preparing it into the desired dosage form according to conventional techniques. The composition of the present invention can be formulated into oral administration formulations, mucosal administration formulations, injectable formulations, inhaled formulations, and topical formulations as needed.

[0143] The polypeptides of this invention are not homologous to known polypeptides, facilitating the synthesis of high-purity polypeptides. Furthermore, the polypeptides of this invention can bind to the FGFR1 receptor to exert biological effects, exhibiting significant therapeutic effects on skin and mucous membrane diseases caused by various factors. These polypeptides can be used to treat acute and chronic gastrointestinal diseases, tumors, and related diseases. The polypeptides of this invention have a small molecular weight and, when administered orally, significantly reduce inflammation and edema, promote the repair of gastrointestinal mucosal damage, and alleviate the pathological development of acute and chronic gastritis and peptic ulcers. They also promote skin wound repair, shorten wound healing time, and regulate immune function. Oral administration is also effective. In addition, the polypeptides of this invention remain effective even after disinfection with iodine preparations or hydrogen peroxide when applied to skin wounds, whereas epidermal growth factor, when applied to skin wounds, will have its structure destroyed after disinfection with iodine preparations or hydrogen peroxide and will not function. Attached Figure Description

[0144] The accompanying drawings are provided for the purpose of further illustrating this application and are not intended to limit the scope of this application.

[0145] Figure 1 The mass spectrum of compound 62 is shown.

[0146] Figure 2 The mass spectrum of compound 63 is shown.

[0147] Figure 3 The mass spectrum of compound 1 is shown.

[0148] Figure 4 The mass spectrum of compound 64 is shown.

[0149] Figure 5 The mass spectrum of compound 65 is shown.

[0150] Figure 6 The mass spectrum of compound 66 is shown.

[0151] Figure 7The mass spectrum of compound 67 is shown.

[0152] Figure 8 The mass spectrum of compound 68 is shown.

[0153] Figure 9 The mass spectrum of compound 69 is shown.

[0154] Figure 10 The mass spectrum of compound 70 is shown.

[0155] Figure 11 The mass spectrum of compound 71 is shown.

[0156] Figure 12 The mass spectrum of compound 72 is shown.

[0157] Figure 13 The mass spectrum of compound 73 is shown.

[0158] Figure 14 A schematic diagram of the solid-phase synthesis steps of peptides is shown.

[0159] Figure 15 The therapeutic effect of compound 1 on a mouse model of chronic atrophic gastritis was demonstrated.

[0160] Figure 16 The study demonstrated the proliferative effect of compound 53 on HaCaT cells.

[0161] Figure 17 The study demonstrated the proliferative effect of compound 1 on HaCaT cells.

[0162] Figure 18 The study demonstrated the proliferative effect of compound 64 on HaCaT cells.

[0163] Figure 19 The study demonstrated the proliferative effect of compound 65 on HaCaT cells.

[0164] Figure 20 The study demonstrated the proliferative effect of compound 66 on HaCaT cells.

[0165] Figure 21 The study demonstrated the proliferative effect of compound 57 on HaCaT cells.

[0166] Figure 22 The study demonstrated the proliferative effect of compound 68 on HaCaT cells.

[0167] Figure 23 The study demonstrated the proliferative effect of compound 69 on HaCaT cells.

[0168] Figure 24 The proliferative effect of compound 70 on HaCaT cells was demonstrated.

[0169] Figure 25 The proliferative effect of compound 71 on HaCaT cells was demonstrated.

[0170] Figure 26 The study demonstrated the proliferative effect of compound 72 on HaCaT cells.

[0171] Figure 27 The study demonstrated the proliferative effect of compound 73 on HaCaT cells.

[0172] Figure 28 The proliferative effect of compound 1 on HMEC-1 cells was demonstrated.

[0173] Figure 29 The proliferative effect of compound 64 on HMEC-1 cells was demonstrated.

[0174] Figure 30 The proliferative effect of compound 71 on HMEC-1 cells was demonstrated.

[0175] Figure 31 The proliferative effect of compound 72 on HMEC-1 cells was demonstrated.

[0176] Figure 32 The proliferative effect of compound 73 on HMEC-1 cells was demonstrated.

[0177] Figure 33 The proliferative effect of compound 63 on RSC96 cells was demonstrated.

[0178] Figure 34 The proliferative effect of compound 1 on RSC96 cells was demonstrated.

[0179] Figure 35 The proliferation-promoting effect of compound 65 on RSC96 cells was demonstrated.

[0180] Figure 36 The proliferative effect of compound 67 on RSC96 cells was demonstrated.

[0181] Figure 37 The effect of compound 68 on the proliferation of RSC96 cells was shown.

[0182] Figure 38 Compound 70 was shown to inhibit the proliferation of RSC96 cells.

[0183] Figure 39 The effect of compound 71 on the proliferation of RSC96 cells was shown.

[0184] Figure 40 The proliferative effect of polypeptide compound 73 on RSC96 cells was demonstrated. Detailed Implementation

[0185] The term "physiologically compatible salt" refers to a salt form that is physiologically compatible (i.e., pharmacologically acceptable) and substantially non-toxic to the individual to whom the compounds of the present invention will be administered. Physiologically compatible salts of the compounds of the present invention include conventional and stoichiometric acid addition salts or base addition salts formed from suitable, non-toxic organic or inorganic acids or inorganic bases.

[0186] The term "subject" refers to an animal, preferably a mammal, and most preferably a human. Specifically, the term "subject" refers to a mammal or human with skin trauma and / or mucosal damage. Those skilled in the art will understand that the repair of skin trauma and / or mucosal damage of the present invention can be applied for cosmetic (i.e., non-therapeutic) and therapeutic purposes. Therefore, the term "skin damage" in this application also includes skin damage repaired for cosmetic purposes, such as wrinkles (e.g., wrinkles caused by ultraviolet radiation), skin lines, cracks, lumps, large pores (e.g., associated with appendage structures such as sweat ducts, sebaceous glands, or hair follicles), or unevenness or roughness, loss of skin elasticity (loss and / or inactivation of functional elastin), sagging (including puffiness around the eyes and jaw), loss of skin firmness, loss of skin tightness, loss of the ability to recover after skin deformation, discoloration (including dark circles), freckles, grayish-yellow skin tone, hyperpigmented skin areas such as age spots and freckles, keratin, abnormal differentiation, hyperkeratosis, degeneration of elastic tissue, destruction of collagen, and other tissue changes in the stratum corneum, dermis, epidermis, vascular system of the skin (e.g., telangiectasia or bifurcated vessels), and subcutaneous tissue, especially other tissue changes in the subcutaneous tissue close to the skin.

[0187] The following description of the present invention is based on specific experiments and is not intended to limit the scope of protection of the present invention.

[0188] Example 1: Chemical Synthesis of Peptides

[0189] The peptide compounds were synthesized using conventional solid-phase synthesis methods, involving multiple cycles of resin swelling, amino acid substitution, deprotection, washing, amino acid activation, condensation, washing, and deprotection, followed by final cleavage and side chain deprotection. This application utilizes a peptide synthesizer for synthesis.

[0190] Table 1. English names, abbreviations, and corresponding Chinese names of solvents and reagents, etc.

[0191] 2-Chlorotrityl Chloride Resin 2-Chlorotriphenylmethyl chloride resin DMF N,N-Dimethylformamide DCM dichloromethane PIP Piperidine HOBt 1-Hydroxybenzotriazole DIPEA N,N-Diisopropylethylamine Methanol methanol tert-Butyl methyl ether Methyl tert-butyl ether TFA Trifluoroacetic acid TIS Triisopropylsilane DIC N,N'-Diisopropylcarbodiimide Ethanol ethanol Aa amino acids

[0192] The following uses compound 1 (Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu) as an example to illustrate the method for the synthesis and purification of compound 1. The method includes steps 1, preparation of fully protected peptide resin; 2, cleavage and deprotection; 3, purification (salt replacement) and lyophilization.

[0193] Step 1: Preparation of fully protected peptide resin

[0194] (1) Preparation of Fmoc-Glu(OtBu)-resin: 13.48 g of 2-Chlorotrityl Chloride Resin (SD = 0.75 mmol / g) and dichloromethane (DCM) were weighed and added sequentially to six synthesis tubes of a peptide synthesizer. The substitution reaction of the first amino acid and the removal of the protecting group Fmoc were carried out using the substitution reaction program set in the peptide synthesizer. The specific reaction process is as follows: The resin was swollen with DCM for 20 minutes and then drained. In an activation flask, Fmoc-Aa(n)-OH (3 eq, 6 mmol) was dissolved in DMF (40 mL), and then DIPEA (7 eq, 14 mmol) was added. The DMF mixed solution of Fmoc-Aa(n)-OH / DIPEA was added to the reaction flask containing the resin and reacted for 1 hour, and then drained. Add 20% MeOH / DMF (40 mL) and react for 30 minutes to seal the end. After draining, wash 3 times with DMF, then remove the protecting group Fmoc with 20% PIP / DMF (v / v), and wash 5 times with DMF solution.

[0195] (2) Preparation of fully protected peptide resin: The circulating water bath temperature was adjusted to 35 degrees Celsius. Using the coupling program set in the peptide synthesizer, amino acids were coupled one by one according to the peptide sequence, starting from the (n-1)th amino acid. The specific reaction process is as follows: Fmoc-Aa(n-1)-OH (3 eq, 6 mmol) and HOBt (3 eq, 6 mmol) were dissolved in DMF (40 mL) in an activation flask, and then DIC (4 eq, 8 mmol) was added to activate the amino acids. The DMF mixture of Fmoc-Aa(n-1)-OH / HOBt / DIC was added to the amino acid resin in the reaction flask for coupling. After reacting for 1 hour, the solvent was removed, and the solid resin was washed 3 times with DMF solution. Then, the protecting group Fmoc was removed with 20% PIP / DMF (v / v) and washed 5 times with DMF solution. The above steps were repeated until the entire amino acid sequence was coupled. The amount of each amino acid and condensing agent is shown in Table 2.

[0196] Step 2, Cutting

[0197] Transfer the resin from the peptide synthesizer to a manual synthesis tube with a sieve plate and wash five times with DCM. Add 200 mL of cleavage agent (TFA:TIS:H2O = 95:2.5:2.5, v / v) to the synthesis tube, and then bubble the reaction under nitrogen (N2) for 1.5–3 hours.

[0198] After the cleavage reaction was complete, the cleavage agent was filtered into a 500 mL round-bottom flask. After vacuum concentration to one-quarter of the original cleavage agent volume, 10 times the current volume of methyl tert-butyl ether was added, and the mixture precipitated to obtain a white solid. The resulting mixture was filtered and washed three times with 50 mL of methyl tert-butyl ether. The crude peptide product was then placed in a vacuum drying oven to remove excess solvent until the crude peptide was in powder form. 11.46 g of crude peptide was obtained, with a crude yield of 61.5%.

[0199] Step 3: Purification (salt replacement) freeze-drying

[0200] (1) Purification of peptides (HPLC)

[0201] A. Chromatographic parameters

[0202] Column: Dynamic axial compression column, 80*250mm; Packing material: Daisogel C18 (SP-100-8-ODS-P)

[0203] Eluent A: 0.1% aqueous solution of trifluoroacetic acid (v / v)

[0204] Elution Buffer B: Acetonitrile

[0205] Flow rate: 180 mL / min

[0206] UV detection wavelength: 220nm

[0207] B. Operating Procedures a) Dissolve the crude peptide in water and / or acetonitrile and filter it through a 0.45 μm filter membrane; b) Inject the sample; c) Elute with an acetonitrile-water mobile phase gradient; d) Collect the target peptide eluent; e) Concentrate by rotary evaporation.

[0208] (2) Polypeptide salt swapping (HPLC)

[0209] A. Chromatographic parameters

[0210] Column: Dynamic axial compression column, 80*250mm; Packing material: Daisogel C18 (SP-100-8-ODS-P)

[0211] Eluent A1: 0.1M acetic acid

[0212] Eluent A2: 0.025M acetic acid – 0.1M ammonium acetate

[0213] Elution Buffer B: Acetonitrile

[0214] Flow rate: 180 mL / min

[0215] UV detection wavelength: 220nm

[0216] B. Operating steps: a) Equilibrate the column with 95% A1 + 5% B; b) Inject the sample; c) Equilibrate the column with 95% A2 + 5% B; d) Elute with gradients of A1 and B; e) Collect the eluent of the target peptide; f) Concentrate by rotary evaporation; g) Freeze-dry.

[0217] Table 2. Amounts of amino acids and condensing agents used in the chemical synthesis of peptides.

[0218]

[0219]

[0220] Other compounds were synthesized in a similar manner to that used for compound 1. Results are shown in Table 3 and other parts of the specification.

[0221] Table 3. Synthesized polypeptide compounds

[0222]

[0223]

[0224]

[0225]

[0226] Note: Double charge peaks indicate that the target molecule has 2 protons, and triple charge peaks indicate that the target molecule has 3 protons; N / A indicates that weighing is difficult and the actual weight is not included.

[0227] Compound 1: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (acetate)

[0228] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 63 H 108 N 18 O 25 S; m / z: 517.25855 ([M+3H]) 3+ ), 775.38204([M+2H] 2+ ), 1549.74923([M+H] + ).

[0229] 1H NMR(600MHz,D2O+MeOD)δ4.63–4.50(m,1H),4.27(t,J=7.3Hz,1H),4.19(dd,J=9.3,5.1Hz,1H ),4.14(t,J=5.5Hz,1H),4.09(q,J=7.2Hz,2H),4.05–3.93(m,9H),3.85–3.76(m,2H),3.75–3. 62(m,4H),2.75(t,J=7.6Hz,4H),2.39–2.21(m,8H),2.15(t,J=7.5Hz,2H),2.03–1.71(m,23H ,AcOH),1.69–1.20(m,16H),1.20–1.13(m,12H),0.68(d,J=6.3Hz,3H),0.62(d,J=6.3Hz,3H).

[0230] Compound 2: Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu

[0231] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 55 H 94 N 16 O 22 m / z: 444.56747([M+3H]) 3+ ),

[0232] 666.34654([M+2H] 2+ ), 1331.68030([M+H] + ).

[0233] Compound 3: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys

[0234] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 55 H 96 N 16 O 21 S; m / z: 450.56546 ([M+3H]) 3+ ), 675.34210([M+2H]2 + ), 1349.67108([M+H] + ).

[0235] Compound 4: Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys

[0236] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 47 H 82 N 14 O 18 m / z: 377.87399([M+3H]) 3+ ), 566.30565([M+2H] 2+ ), 1131.59986([M+H] + ).

[0237] Compound 5: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys

[0238] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 47 H 81 N 13 O 19 S; m / z: 582.78356 ([M+2H]) 2+ ), 1164.55736([M+H] 2+ ).

[0239] Compound 6: Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys

[0240] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 39 H 67 N 11 O 16 m / z: 473.74506([M+2H]) 2+ ), 946.48291([M+H] 2+ ).

[0241] Compound 7: Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu

[0242] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 38 H 65 N 11 O 16 m / z: 466.73868([M+2H]) 2+ ), 932.46713([M+H] + ).

[0243] Compound 8: Ser-Met-Gln-Ala-Ser-Leu

[0244] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C25 H 45 N7O 10 S; m / z: 636.30254 ([M+H] + ).

[0245] Compound 9: Gln-Ala-Ser-Leu (acetate)

[0246] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 17 H 31 N5O7; m / z: 418.22972 ([M+H]) + ).

[0247] 1 H NMR(600MHz,D2O)δ4.43–4.33(m,2H),4.20–4.15(m,1H),4.00(t,J=6.6Hz,1H),3.85–3.76(m,2H),2.46–2.35( m,2H),2.17–2.04(m,2H),2.00–1.96(m,2H,AcOH),1.58–1.51(m,3H),1.37(d,J=7.2Hz,3H),0.89–0.76(m,6H).

[0248] Compound 10: Gly-Lys-Ala-Glu

[0249] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 16 H 29 N5O7; m / z: 404.21472 ([M+H]) + ).

[0250] Compound 11: Ser-Met(O)-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (acetate)

[0251] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 63 H 108 N 18 O 26 S; m / z: 522.58959([M+3H]) 3+ ), 783.37985([M+2H] 2+ ), 1565.74624([M+H] + ).

[0252] 1H NMR(600MHz,D2O)δ4.59–4.46(m,3H),4.37(t,J=5.6Hz,1H),4.32–4.22(m,7H),4.22–4.17(m ,3H),4.16–4.10(m,2H),3.98–3.92(m,2H),3.90(s,1H),3.88–3.77(m,3H),2.94(t,J=7.5Hz ,5H),2.90–2.81(m,1H),2.66(s,3H),2.41–2.19(m,9H),2.17–1.67(m,23H,AcOH),1.66–1.5 3(m,7H),1.48–1.36(m,4H),1.35–1.32(m,12H),0.87(d,J=5.6Hz,3H),0.81(d,J=5.7Hz,3H).

[0253] Compound 12: Ser-Val-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (acetate)

[0254] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 63 H 108 N 18 O 25 m / z: 506.59990([M+3H]) 3+ ), 759.39412([M+2H] 2+ ), 1517.77125([M+H] + ).

[0255] 1 H NMR(600MHz,D2O)δ4.37(t,J=5.5Hz,1H),4.33–4.23(m,7H),4.22–4.11(m,6H),3.98–3.79(m,6H),2.95(t,J=7.5Hz,4H),2.41–2.25(m,8H),2. 08–2.00(m,5H),1.99–1.68(m,15H,AcOH),1.67–1.54(m,7H),1.50–1.3 7(m,4H),1.37–1.33(m,12H),0.92–0.86(m,9H),0.82(d,J=5.7Hz,3H).

[0256] Compound 13: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Gln (acetate)

[0257] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 63 H 109 N 19 O 24 S; m / z: 516.92919 ([M+3H]) 3+ ), 774.88810([M+2H] 2+ ), 1548.75961([M+H] + ).

[0258] 1 H NMR(600MHz,D2O)δ4.47(dd,J=8.3,6.1Hz,1H),4.39–4.34(m,1H),4.31–4.16(m,10H),4.16– 4.08(m,2H),3.97–3.94(m,2H),3.94–3.79(m,4H),2.94(t,J=7.6Hz,4H),2.60–2.47(m,2H), 2.40–2.22(m,8H),2.10–1.98(m,9H),1.98–1.84(m,13H,AcOH),1.84–1.67(m,4H),1.67–1.5 4(m,7H),1.48–1.37(m,4H),1.36–1.32(m,12H),0.87(d,J=5.8Hz,3H),0.82(d,J=5.8Hz,3H).

[0259] Compound 14: Ser-Met-Gln-Ala-Ser-Leu-Gln-Ala-Gln-Ala-Lys-Gly-Lys-Ala-Glu (acetate)

[0260] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 63 H 110 N 20 O 23 S; m / z: 516.60130([M+3H]) 3+ ), 774.39599([M+2H] 2+ ), 1547.77410([M+H] + ).

[0261] 1H NMR(600MHz,D2O)δ4.69–4.61(m,1H),4.13(t,J=7.3Hz,1H),4.09–3.93(m,4H),3.92– 3.78(m,10H),3.74–3.65(m,2H),3.64–3.51(m,4H),2.98–2.96(m,1H),2.95–2.92(m,2 H),2.65–2.59(m,4H),2.28–1.97(m,10H),1.89–1.57(m,21H,AcOH),1.57–1.18(m,11H ),1.18–1.08(m,4H),1.07–1.00(m,12H),0.55(d,J=6.4Hz,3H),0.50(d,J=6.4Hz,3H).

[0262] Compound 15: Ser-Met-Gln-Ala-Ser-Ala-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu

[0263] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 60 H 102 N 18 O 25 S; m / z: 503.24185 ([M+3H]) 3+ ), 754.35857([M+2H] 2+ ), 1507.70677([M+H] + ).

[0264] Compound 16: Ser-Ala-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu

[0265] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 61 H 104 N 18 O 25 m / z: 497.25701([M+3H]) 3+ ), 745.38093([M+2H] 2+ ), 1489.74746([M+H] + ).

[0266] Compound 17: Ser-Leu-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu

[0267] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 64 H 110 N 18 O 25 m / z: 766.40505([M+2H]) 2+ ).

[0268] Compound 18: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Ala-Gly-Lys-Ala-Glu

[0269] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 60 H 101 N 17 O 25 S; m / z: 746.85331([M+2H]) 2+ ).

[0270] Compound 19: Ser-Met-Gln-Ala-Ser-Leu-Ala-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu

[0271] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 61 H 106 N 18 O 23 S; m / z: 497.92179([M+3H]) 3+ ), 746.37833([M+2H] 2+ )1491.74166([M+H] + ).

[0272] Compound 20: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Ala-Ala-Lys-Gly-Lys-Ala-Glu

[0273] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 61 H 106 N 18 O 23 S; m / z: 497.92359 ([M+3H]) 3+ ), 746.38084([M+2H] 2+ )1491.74509([M+H] + ).

[0274] Compound 21: Ser-Met-Ala-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu

[0275] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 61 H 105 N 17 O 24 S; m / z: 498.25060 ([M+3H]) 3+ ), 746.87141([M+2H] 2+ ).

[0276] Compound 22: Ser-Ile-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu

[0277] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 64 H 110 N 18 O 25 m / z: 511.27255([M+3H]) 3+ ), 766.40318([M+2H] 2+ ), 1531.78999([M+H] + )

[0278] Compound 23: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Asp

[0279] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 62 H 106 N 18 O 25 S; m / z: 512.58493 ([M+3H]) 3+ ), 768.37218([M+2H] 2+ )1535.72417([M+H] + ).

[0280] Compound 24: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Asn

[0281] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 62 H 107 N 19 O24 S; m / z: 512.25851([M+3H] 3+ ), 767.88243([M+2H] 2+ ), 1534.34795([M+H] + ).

[0282] Compound 25: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Arg-Ala-Glu

[0283] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 63 H 108 N 20 O 25 S; m / z: 526.59167 ([M+3H]) 3+ ), 789.38318([M+2H] 2+ ), 1577.76111([M+H] + ).

[0284] Compound 26: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Ala-Ala-Glu

[0285] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 60 H 101 N 17 O 25 S; m / z: 746.85430 ([M+2H]) 2+ ), 1492.68936([M+H] + )

[0286] Compound 27: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Ala

[0287] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 61 H 106 N 18 O 23 S; m / z: 497.92090 ([M+3H]) 3+ ), 746.37592([M+2H] 2+ ), 1491.74463([M+H] + ).

[0288] Compound 28: Ser-Met-Gln-Ala-Ala-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu

[0289] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 63 H 108 N 18 O 24 S; m / z: 511.92444([M+3H]) 3+ ), 767.38306([M+2H] 2+ ), 1533.75671([M+H] + ).

[0290] Compound 29: Ala-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (acetate)

[0291] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 63 H 108 N 18 O 24 S; m / z: 511.92638 ([M+3H]) 3+ ), 767.38435([M+2H] 2+ ), 1533.75280([M+H] + ).

[0292] 1 H NMR(600MHz,D2O)δ4.38(dd,J=8.4,6.0Hz,1H),4.32(t,J=5.6Hz,1H),4.26–4.12(m,10H),4.08(dd ,J=8.5,4.9Hz,1H),4.00(q,J=7.1Hz,1H),3.90–3.84(m,1H),3.84–3.73(m,3H),2.89(t,J=7.6Hz, 4H),2.54–2.42(m,2H),2.37–2.21(m,8H),2.05–1.95(m,8H),1.95–1.49(m,25H,AcOH),1.43(d,J= 7.1Hz,3H),1.41–1.31(m,4H),1.30(t,J=7.2Hz,12H),0.83(d,J=5.8Hz,3H),0.77(d,J=6.0Hz,3H).

[0293] Compound 30: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Arg-Gly-Lys-Ala-Glu

[0294] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 63 H 108 N 20 O 25 S;526.59256([M+3H] 3+ ), 789.38355([M+2H] 2+ )1577.74446([M+H] + ).

[0295] Compound 31: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-His-Ala-Glu

[0296] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 63 H 103 N 19 O 25 S; m / z: 520.24450 ([M+3H]) 3+ ), 779.86149([M+2H] 2+ ), 1558.70931([M+H] + ).

[0297] Compound 32: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-His-Gly-Lys-Ala-Glu

[0298] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 63 H 103 N 19 O 25 S; m / z: 520.24531 ([M+3H]) 3+ ), 779.86349([M+2H] 2+ ), 1558.71094([M+H] + ).

[0299] Compound 33: Ser-Met-Gln-Ala-Ser-Leu-Leu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu

[0300] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 64 H112 N 18 O 23 S; m / z: 767.38324 ([M+2H]) 2+ ), 1533.75610([M+H] + ).

[0301] Compound 34: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Leu-Ala-Lys-Gly-Lys-Ala-Glu (acetate)

[0302] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 64 H 112 N 18 O 23 S; m / z: 767.39618 ([M+2H]) 2+ ), 1533.79517([M+H] + ).

[0303] 1 H NMR(600MHz,D2O)δ4.39(dd,J=8.2,6.2Hz,1H),4.30(dd,J=9.3,5.1Hz,1H),4.26(t,J=5.4Hz,1H),4.23–4.04(m ,11H),3.89(d,J=4.7Hz,2H),3.87–3.74(m,4H),2.86(t,J=7.7Hz,4H),2.50–2.40(m,2H),2.40–2.32(m,4H),2.2 6(t,J=7.5Hz,2H),2.13–2.05(m,1H),2.00–1.96(m,5H),1.96–1.83(m,13H,AcOH),1.78–1.60(m,4H),1.60–1.5 1(m,8H),1.51–1.43(m,2H),1.42–1.29(m,4H),1.29–1.26(m,12H),0.80(t,J=5.6Hz,6H),0.74(d,J=6.0Hz,6H).

[0304] Compound 35: Ser-Met-Gln-Ala-Ser-Leu-Gln-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu

[0305] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 63 H 109 N 19 O 24S; m / z: 774.88964 ([M+2H]) 2+ ), 1548.76276([M+H] + ).

[0306] Compound 36: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Gln-Ala-Lys-Gly-Lys-Ala-Glu

[0307] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 63 H 109 N 19 O 24 S; m / z: 516.92993 ([M+3H]) 3+ ), 774.88916([M+2H] 2+ )1548.76034([M+H] + ).

[0308] Compound 37: Ser-Met-Glu-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu

[0309] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 63 H 107 N 17 O 26 S; m / z: 775.87388([M+2H]) 2+ ), 1550.72354([M+H] + ).

[0310] Compound 38: Ser-Met-Gln-Ala-Ser-Leu-Asp-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu

[0311] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 62 H 106 N 18 O 25 S; m / z: 768.37273 ([M+2H]) 2+ ), 1535.72499([M+H] + ).

[0312] Compound 39: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Asp-Ala-Lys-Gly-Lys-Ala-Glu

[0313] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 62 H 106 N 18 O 25 S; m / z: 768.37189([M+2H]) 2+ ), 1535.72715([M+H] + ).

[0314] Compound 40: Thr-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu

[0315] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 64 H 110 N 18 O 25 S; m / z: 521.92978 ([M+3H]) 3+ ), 782.38824([M+2H] 2+ ), 1563.75498([M+H] + ).

[0316] Compound 41: Ser-Met-Gln-Ala-Thr-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu

[0317] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 64 H 110 N 18 O 25 S; m / z: 521.92871([M+3H]) 3+ ), 782.38721([M+2H] 2+ ), 1563.76697([M+H] + ).

[0318] Compound 42: Ser-Met-Gln-Ala-Ser-Val-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu

[0319] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 62 H 106 N 18 O 25 S; m / z: 768.37357 ([M+2H]) 2+ ).

[0320] Compound 43: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ser-Glu-Ala-Lys-Gly-Lys-Ala-Glu

[0321] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 63 H 108 N 18 O 26 S; m / z: 522.58964 ([M+3H]) 3+ ), 783.37864([M+2H] 2+ ).

[0322] Compound 44: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ser-Lys-Gly-Lys-Ala-Glu

[0323] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 63 H 108 N 18 O 26 S; m / z: 783.37737([M+2H]) 2+ ), 1565.72717([M+H] + ).

[0324] Compound 45: Glu-Ala-Glu-Ala (acetate)

[0325] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 16 H 26 N4O9; m / z: 419.17728 ([M+H]) + ).

[0326] 1 H NMR (600MHz, DMSO-d6) δ8.60(d,J=7.1Hz,1H),8.27(d,J=7.8Hz,1H),7.90(d,J=6.8Hz,1H),4.29(p,J=7.0Hz,1H),4.19(td,J=8.3,5.1Hz,1H),4.02 (p,J=7.1Hz,1H),3.66(t,J=6.3Hz,1H),2.31(t,J=7.6Hz,2H),2.23(t,J= 7.9Hz,2H),1.95–1.79(m,5H,AcOH),1.79–1.70(m,1H),1.27–1.21(m,6H).

[0327] Compound 46: Glu-Ala-Glu-Ala-Lys-Gly-Lys

[0328] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 30 H 53 N9O 12 m / z: 732.38880([M+H]) + ).

[0329] Compound 47: Thr-Ala-Ser-Thr-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu

[0330] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 58 H 100 N 16 O 24 m / z: 469.24518([M+3H]) 3+ ), 703.36326([M+2H] 2+ )1405.71314([M+H] + ).

[0331] Compound 48: Ser-Thr-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu (acetate)

[0332] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 62 H 106 N 18 O 26 m / z: 507.25973([M+3H]) 3+ ), 760.38380([M+2H] 2+ ), 1519.74995([M+H] + ).

[0333] 1H NMR(600MHz,D2O)δ4.33–4.27(m,2H),4.25–4.11(m,12H),4.08(dd,J=8.6,4.9Hz,1H),3. 95–3.89(m,2H),3.89–3.85(m,1H),3.84–3.73(m,3H),2.89(t,J=7.6Hz,4H),2.39–2.22( m,8H),2.04–1.86(m,20H,AcOH),1.86–1.63(m,5H),1.63–1.46(m,7H),1.43–1.32(m,4H) ,1.31–1.27(m,12H),1.13(d,J=6.3Hz,3H),0.81(d,J=6.2Hz,3H),0.76(d,J=6.2Hz,3H).

[0334] Compound 49: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Gln-Asp

[0335] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 67 H 114 N 20 O 27 S; m / z: 555.27329 ([M+3H]) 3+ ), 832.40392([M+2H] 2+ ), 1663.79211([M+H] + ).

[0336] Compound 50: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Gln-Glu

[0337] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 68 H 116 N 20 O 27 S; m / z: 559.94388 ([M+3H]) 3+ ), 839.40987([M+2H] 2+ ), 1677.80026([M+H] + ).

[0338] Compound 51: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Gln-Leu

[0339] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 69 H 119 N 19 O 26 S; m / z: 554.95315 ([M+3H]) 3+ ), 831.92378([M+2H] 2+ ).

[0340] Compound 52: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Gln-Ala

[0341] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 66 H 113 N 19 O 26 S; m / z: 540.93567 ([M+3H]) 3+ ), 810.89807([M+2H] 2+ ).

[0342] Compound 53: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Lys-Gln-Asp

[0343] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 73 H 126 N 22 O 28 S; m / z: 448.73124 ([M+4H]) 4+ ), 597.97133([M+3H] 3+ ), 896.45075([M+2H] 2+ ), 1791.88031([M+H] + ).

[0344] Compound 54: Ala-Glu-Pro-Val-Pro-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu

[0345] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 67 H 111 N 17 O 24 m / z: 513.60834([M+3H]) 3+ ), 769.90656([M+2H]2+ ), 1538.80615([M+H] + ).

[0346] Compound 55: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu

[0347] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 75 H 123 N 19 O 26 m / z: 569.63794 ([M+3H]) 3+ ), 853.95032([M+2H] 2+ ), 1706.89331([M+H] + ).

[0348] Compound 56: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Ala-Lys-Ala-Glu

[0349] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 64 H 110 N 18 O 25 S; m / z: 521.93003([M+3H]) 3+ ), 782.38948([M+2H] 2+ ), 1563.76203([M+H] + ).

[0350] Compound 57: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Pro-Lys-Ala-Glu (acetate)

[0351] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 66 H 112 N 18 O 25 S; m / z: 530.60034 ([M+3H]) 3+ ), 795.39502([M+2H] 2+ ), 1589.78271([M+H] + ).

[0352] 1H NMR(600MHz,D2O)δ4.49(dd,J=9.1,5.2Hz,1H),4.42(dd,J=8.4,5.9Hz,1H),4.31(q,J=7.4,6.4H z,2H),4.26–4.13(m,9H),4.11–4.05(m,2H),3.94–3.86(m,2H),3.83–3.69(m,3H),3.55–3.47(m ,1H),2.93–2.87(m,4H),2.54–2.42(m,2H),2.36–2.16(m,9H),2.04–1.93(m,9H),1.93–1.49(m, 28H,AcOH),1.43–1.32(m,4H),1.31–1.25(m,12H),0.82(d,J=5.7Hz,3H),0.76(d,J=5.7Hz,3H).

[0353] Compound 58: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Lys-Gln-Glu

[0354] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 74 H 128 N 22 O 28 S; m / z: 452.23230([M+4H]) 4+ ), 602.64038([M+3H] 3+ ), 903.45508([M+2H] 2+ ), 1805.90295([M+H] + ).

[0355] Compound 59: Arg-Lys-Asp-Val-Tyr-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu

[0356] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 68 H 112 N 20 O 24 m / z: 399.21298([M+4H]) 4+ ), 531.94670([M+3H] 3+ ), 797.41529([M+2H] 2+ ), 1593.81299([M+H] + ).

[0357] Compound 60: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ser-Glu (acetate)

[0358] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 63 H 108 N 18 O 26 S; m / z: 522.58909([M+3H]) 3+ ), 783.37789([M+2H] 2+ ), 1565.73801([M+H] + ).

[0359] 1 H NMR(600MHz,D2O)δ4.45–4.39(m,1H),4.37(t,J=5.5Hz,1H),4.34–4.26(m,2H),4.25–4.06(m,10H),3.91–3.90(m,2 H),3.88–3.86(m,1H),3.85–3.80(m,2H),3.79–3.74(m,3H),2.89(t,J=7.5Hz,4H),2.54–2.43(m,1H),2.39–2.22(m, 7H),2.06–1.96(m,8H),1.95–1.92(m,23H,AcOH),1.91–1.87(m,2H),1.86–1.73(m,2H),1.72–1.65(m,1H),1.62–1. 54(m,6H),1.54–1.48(m,1H),1.45–1.31(m,4H),1.30(d,J=7.2Hz,9H),0.82(d,J=5.9Hz,3H),0.77(d,J=5.9Hz,3H).

[0360] Compound 61: Glu-Ala-Glu-Ala-Ala-Gly-Lys-Ala-Glu (acetate)

[0361] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 35 H 58 N 10 O 16 m / z: 438.21012([M+2H]) 2+ ), 875.40922([M+H] + ).

[0362] 1H NMR(600MHz,D2O)δ4.29–4.15(m,7H),4.11(dd,J=8.6,4.9Hz,1H),3.95(t,J=6.5Hz,1H),3.87–3.77(m,2H),2.88(t,J=7.6Hz,2H),2.39–2.25(m, 7H),2.10–1.94(m,9H,AcOH),1.91–1.78(m,2H),1.78–1.69(m,1H),1.69 –1.62(m,1H),1.62–1.53(m,2H),1.37–1.30(m,2H),1.30–1.25(m,14H).

[0363] Compound 62: Phe-Asp-Ala-Leu-Lys-Gln-Gln-Phe-Gln-Ala-Phe-Gln-Leu-Glu

[0364] High-resolution mass spectrometry (Orbitrap Exploris) m / z: 571.62579 ([M+3H]) 3+ ),856.93494([M+2H] 2+ )

[0365] Compound 63: His-Cys-Leu-Ala-Gly-Leu-Lys-Lys-Asp-Leu-Glu-Asp-Leu-Glu

[0366] High-resolution mass spectrometry (Orbitrap Exploris) m / z: 528.60779 ([M+3H]) 3+ ),792.40802([M+2H] 2+ )

[0367] Compound 54: Glu-Ile-Asn-Gln-Leu-Glu-Leu-Ile-Lys-Gln-Ala-Ser-Ile

[0368] High-resolution mass spectrometry (Orbitrap Exploris) m / z 500.62137 ([M+3H]) 3+ ),749.92682([M+2H] 2+ ),1499.85291([M+H] + )

[0369] Compound 65: Ala-Ala-Arg-Leu-Ala-Asp-Glu-Leu-Arg-Ala-Glu

[0370] High-resolution mass spectrometry (Orbitrap Exploris) m / z: 405.55411 ([M+3H]) 3+ ),607.82733([M+2H] 2+ ),1214.64624([M+H] + )

[0371] Compound 66: Glu-Thr-Leu-Gln-Arg-Lys-Asn-Lys-Glu

[0372] High-resolution mass spectrometry (Orbitrap Exploris) m / z: 382.54669 ([M+3H]) 3+ ),573.31622([M+2H] 2+ ),1146.61548([M+H] + )

[0373] Compound 67: Val-Asp-Ala-Ala-Val-Leu-Glu-Lys-Leu-Glu

[0374] High-resolution mass spectrometry (Orbitrap Exploris) m / z: 543.80505 ([M+2H]) 2+ ),1086.60242([M+H] + )

[0375] Compound 68: Ala-Ala-Val-Leu-Asp-Lys-Leu-Glu

[0376] High-resolution mass spectrometry (Orbitrap Exploris) m / z: 429.74985 ([M+2H]) 2+ ),858.49243([M+H] + )

[0377] Compound 69: Ala-Ala-Val-Leu-Glu-Lys-Leu-Glu

[0378] High-resolution mass spectrometry (Orbitrap Exploris) m / z: 436.75772 ([M+2H]) 2+ ),872.50806([M+H] + )

[0379] Compound 70: Lys-Phe-Tyr-Ser-Gln-Ser-Thr-Ala-Ser-Ser-Ser-Tyr-Ala-Tyr-Pro-Ser-His-Phe-Gly-Pro-Ala-Gly-Phe-Ser-Gly-Ser-His-Ser

[0380] High-resolution mass spectrometry (Orbitrap Exploris) m / z: 736.58075 ([M+4H]4+), 981.77148 ([M+3H]4+). 3+ ),1472.15320([M+2H] 2+ )

[0381] Compound 71: Val-Asp-Ala-Ala-Val-Ile-Glu-Lys-Ile-Glu

[0382] High-resolution mass spectrometry (Orbitrap Exploris) m / z: 543.80481 ([M+2H]) 2+ ),1086.60217([M+H] + )

[0383] Compound 72: Val-Asp-Ala-Ala-Met-Val-Leu-Leu-Thr-Arg

[0384] High-resolution mass spectrometry (Orbitrap Exploris) m / z: 544.80920 ([M+2H]) 2+ ),1088.61121([M+H] + )

[0385] Compound 73: Val-Asp-Ala-Ala-Val-Leu-Met-Leu-Arg-Thr

[0386] High-resolution mass spectrometry (Orbitrap Exploris) m / z: 544.80945 ([M+2H]) 2+ ),1088.61169([M+H] + )

[0387] Example 2: FGFR receptor binding assay: FGFR1 protein target affinity test

[0388] The affinity of the peptide compound prepared in this invention for FGFR1 was tested using an FGFR1 allosteric inhibitor (Sigma product number SSR128129E) as a positive control.

[0389] The FGFR1 affinity screening was carried out as follows: An appropriate concentration of FGFR1 solution was taken and an appropriate concentration of the positive compound SSR128129E (Sigma) was added. Then, the sample solution of the polypeptide compound of the present invention, which was freeze-dried into powder and dissolved with protein buffer, was added respectively. After incubation at room temperature for 50 min, ultrafiltration screening was carried out to obtain solutions with different treatments. After adding an appropriate volume of acetonitrile to precipitate proteins, the supernatant was taken by centrifugation for mass spectrometry analysis.

[0390] Affinity screening conditions: The one-dimensional liquid phase condition was that the chromatographic column was a PolyLC chromatographic column, the mobile phase A was KH2PO4, NaCl, pH 7.5, B was acetonitrile, the column temperature was 8 °C, the flow rate was 1 mL / min, and an appropriate volume was taken for injection; the two-dimensional liquid phase condition was that the chromatographic column was BONUSRRHD, the mobile phase A was 0.1% formic acid aqueous solution, B was 0.1% formic acid acetonitrile, the column temperature was 60 °C, the flow rate was 0.3 mL / min, and the injection volume was 40 uL. Gradient elution was used: 98% A (0 - 1 min), 98% - 10% A (1 - 6 min), 10% A (6 - 7.5 min), 10% - 98% A (7.5 - 8 min), 98% A (8 - 9.5 min). Mass spectrometry conditions: Agilent 6530 Q-Tof, ESI ion source, voltage 3.5 KV, mass-to-charge ratio scanning range m / z = 200 - 3000, the acquisition mode was positive ion scanning, the ion source temperature was 350 °C, the desolvation temperature was 300 °C, and the nitrogen gas flow rate was 8 L / min.

[0391] Through the affinity screening results, it was found that Compound 1 and Compounds 62 - 73 had affinity for FGFR1.

[0392] Table 4. Screening results of polypeptide compounds with affinity binding to FGFR1

[0393] Positive 4～5 Compound 62 1.0～3 Compound 63 1.0～3 Compound 1 1.0～3 Compound 64 1.0～3 Compound 65 1.0～3 Compound 66 1.0～3 Compound 67 1.0～3 Compound 68 1.0～3 Compound 69 1.0～3 Compound 70 1.0～3 Compound 71 1.0～3 Compound 72 1.0～3 Compound 73 1.0～3

[0394] * The Cb / Ct ratio refers to the amount of the compound in the lower layer (mass spectrometry signal intensity) compared to the amount of the compound in the upper layer (mass spectrometry signal intensity) during the ultracentrifugation affinity screening. The larger the Cb / Ct ratio, the stronger the affinity.

[0395] Example 3: Anti-ulcer effect of the polypeptide compound of the present invention on an ethanol-induced mouse gastric ulcer model

[0396] Experimental animals: 6-week-old C57BL / 6JGPt male mice, weighing about 20 g per mouse, 10 mice in each group, Chengdu Yakang Biotech Co., Ltd., animal license number: SCXK (Chuan) 2020 - 034.

[0397] Experimental methods:

[0398] After the experimental animals were grouped, they were given medication according to Table 5 one day before the experiment. The model group was given 200 μl of pure water, and the other drug groups were given 200 μl of drug solution. After that, all animals were fasted but allowed to drink water for 24 hours.

[0399] One hour after administration on the second day, mice in each group were orally administered 9 μl / g of anhydrous ethanol to induce a gastric model. One hour later, the animals were sacrificed by cervical dislocation, the gastric cardia and pylorus were ligated, and the entire stomach was harvested. 1 mL of 1% formaldehyde solution was injected into the stomach through the proventriculus, the cardia was ligated, and the stomach was immediately placed in 1% formaldehyde solution after removal. After soaking for 30 minutes, the stomach tissue was removed, cut along the greater curvature, and the stomach contents were rinsed clean with physiological saline. The stomach was then laid flat to observe and measure the damage to the gastric mucosa, calculate the ulcer index and ulcer inhibition rate, and take panoramic photographs of the stomach. Finally, the stomach tissue was fixed by immersion in formalin.

[0400] Ulcer Index Calculation Method: For linear lesions longer than 1 mm, measure their length and score 1 point per millimeter; if their width is greater than 1 mm, double the score based on the width in millimeters; if the length is less than 1 mm, score 0.5 points. Add the scores together to obtain the ulcer index of the animal.

[0401] Ulcer inhibition rate % = (Ulcer index of model group - Ulcer index of treatment group) / Ulcer index of model group × 100%.

[0402] Statistical methods: The ulcer index is expressed as mean ± standard deviation; the ulcer inhibition rate is calculated using the median and mean ulcer indices of each treatment group and simulation group; data are statistically analyzed using Excel, and the differences in gastric ulcer index are analyzed using an independent samples t-test. Table 5 shows the relative ulcer inhibition rate results of the compounds of this invention.

[0403] Table 5. Antiulcer activity of the compounds of the present invention after a single dose in a mouse ethanol-induced model.

[0404]

[0405] *Note:

[0406] 1. The anti-ulcer activity of each compound was determined through multiple batches of experiments. For ease of comparison, the anti-ulcer activity is expressed as the average of the relative ulcer inhibition rate (with compound 1 as the control group in each batch of experiments), i.e., relative ulcer inhibition rate = (ulcer inhibition rate of the tested compound) / (ulcer inhibition rate of compound 1).

[0407] 2. ND indicates that no test has been performed.

[0408] Example 4: Pharmacodynamic study of the effect of the polypeptide compound of the present invention on the healing of acute mechanical skin injury in rats.

[0409] SPF-grade SD rats, weighing 180–230g, were housed in clean, sterilized cages. Water, feed, and bedding were provided daily at regular intervals, and the temperature was maintained at 22℃ with a humidity of 55%–65%. The rats were allowed to acclimatize for one week. Animals were then randomly assigned to two groups: a model control group (physiological saline) and a Jin Yintai control group (40 IU / cm²). 2 Shenzhen Huashengyuan Gene Engineering Development Co., Ltd.), and the tested peptide treatment group (40μg / cm). 2 Six rats were placed in each group. After successful anesthesia with intraperitoneal injection of 3% sodium pentobarbital, the hair 1 cm from the edge of the wound was trimmed. The wound area was first disinfected with povidone-iodine, and then locally disinfected with 75% alcohol. A circular full-thickness skin wound of 1.5 cm × 1.5 cm (diameter 1.5 cm) was made along the midline of the spine, extending 4 cm down the back from the midpoint of the ear line to the neck, reaching the muscle layer, to form an animal model of acute mechanical injury. After modeling, the rats were housed individually with their wounds exposed. During dressing changes, the wound was first cleaned with povidone-iodine, then rinsed with sterile saline and dried. Except for the model group, 40 μL of the corresponding drug solution was applied topically to the wounds of rats in other groups once a day. On days 0, 5, 10, and 14 of drug administration, images of the wounds of each group of rats were taken. The wound area was calculated using image analysis software (Image J), ​​and the wound healing rate was then calculated according to the formula.

[0410] The results showed that peptides 68, 67, and 1 all tended to promote wound healing. The results are shown in Table 6.

[0411] Table 6: Effects of representative compounds of this invention on promoting wound healing

[0412] Model control group 8.31±2.12 27.18±3.91 76.07±6.84 Jin Yintai control group 25.35±5.24 59.93±5.88** 86.99±5.42* Group 68 of compounds 29.26±6.46 60.97±2.87** 88.42±4.79* Group 67 of compounds 30.40±3.35 61.42±5.73** 90.87±3.94* Group 1 of compounds 31.68±3.48 63.20±3.87** 91.43±2.87*

[0413] Note: * indicates that p < 0.05 compared to the model group.

[0414] Example 5: Therapeutic effect of compound 1 on a mouse model of chronic atrophic gastritis

[0415] Methods: Chronic atrophic gastritis in mice was modeled using MNNG (N-methyl-N-nitro-N-nitrosoguanidine) combined with ranitidine. Mice were allowed free access to an aqueous solution containing MNNG (100 mg / ml), while simultaneously receiving ranitidine (8 mg / ml) via gavage at a fixed time each day for 20 weeks. After 20 weeks of modeling, in addition to drinking ordinary distilled water, mice were administered compound 1 (5 mg / kg) via gavage daily. The therapeutic effect of compound 1 on chronic atrophic gastritis was observed after 2 weeks of administration.

[0416] Results: Histological staining showed that the gastric glandular structure in the gastric body and antrum of the model group mice was disordered, accompanied by a decrease in the number of gastric acid cells (H+-K+-ATPase positive) and a decrease in the mucosal epithelial height of the gastric antrum. After 2 weeks of treatment with compound 1, compared with the model group, the gastric gland structure of mice in the compound 1 group returned to normal, the number of gastric acid cells increased significantly, and the mucosal height of the gastric antrum basically returned to normal. (See attached results). Figure 15 These results indicate that compound 1 can promote the repair of chronic atrophic gastritis in mice.

[0417] Example 6: The promoting effect of the polypeptide compound of the present invention on the proliferation of HaCAT cells

[0418] Experimental Methods: Human immortalized keratinocytes (HaCaT cells) were passaged at a concentration of 1.0×10⁵–5.0×10⁵ / mL and cultured at 37℃ and 5% CO₂ for 24–36 hours for biological activity assay. Cells were digested with 0.25% trypsin for 5 min, and digestion was terminated by adding at least one volume of 1640 whole blood medium. The cell suspension was collected, centrifuged at 1000 RPM for 3 min, the supernatant was discarded, and the cells were resuspended in 2 mL of 1640 whole blood medium. 20 μL of the cell suspension was stained with AOPI, and the cell concentration was determined using a cell counter. A 5×10⁴ / mL concentration of 1640 medium with 10% serum was prepared and seeded into 96-well cell culture plates at 100 μL per well (5000 cells / well), and cultured overnight at 37℃ and 5% CO₂.

[0419] After 24 hours, the original culture medium was discarded, and 100 μL of 1% serum-concentrated 1640 medium was added to prepare solutions of different concentrations of polypeptide compounds, bringing the final concentrations of the tested polypeptide compounds to 0.2, 0.4, and 0.8 μg / mL, respectively. An EGF control group was set up, containing 100 μL of recombinant human epidermal growth factor (EGF) solution prepared with 1% serum-concentrated 1640 medium, with a final concentration of 100 ng / mL. A model control group was also set up, containing an equal volume of 1% serum-concentrated 1640 medium. Cells were cultured at 37℃ and 5% CO2 for 24 h, 48 h, and 72 h, and the proliferation of the HaCaT cell line was detected using a CCK8 assay kit.

[0420] The test results are as follows Figures 16 to 27 As shown, peptide compounds 74, 73, 72, 71, 70, 69, 68, 67, 66, 65, 1, 64, and 63 exhibited proliferative effects on HaCaT cells at low concentrations (i.e., 0.2–0.8 μg / mL). (* indicates P < 0.05; ** indicates P < 0.01).

[0421] The results showed that most of the H25 peptides of the present invention had a significant proliferative effect on HaCaT cells, and the effect was significantly better than that of the EGF group (100ng / mL).

[0422] Example 7: The promoting effect of the polypeptide compound of the present invention on the proliferation of HMEC-1 cells

[0423] Human microvascular endothelial cells (HMEC-1 cells) were cultured in 10% serum at 37°C and 5% CO2, with the medium changed every 1–2 days to maintain a cell concentration of 4 × 10⁻⁶ cells / day. 6 Cells were passaged at a density of 10 cells / mL. Cells were collected and reconstituted into 5 × 10⁶ cells / mL culture medium. 4 Cells / mL; 100 μL (5000 cells / well) was seeded into 96-well cell culture plates and cultured at 37°C and 5% CO2 until cell adhesion. The polypeptide compound of this invention was prepared into test concentrations (0.05 μg / mL, 0.2 μg / mL, 0.8 μg / mL) using 0% serum medium as the experimental group. A positive control (300 ng / mL) was prepared using the same method and added. An equal volume of 0% serum-free medium was added to the control group. Cells were added to 5 replicates and incubated at 37°C and 5% CO2 for 48 hours. Cell proliferation was detected using CCK-8 assay: the old medium was removed, and serum-free medium containing 10% CCK-8 was added to each well. After incubation for 2 hours, the absorbance was measured at 450 nm using a microplate reader.

[0424] The test results are as follows Figures 28 to 32 As shown, peptide compounds 74, 72, and 1 all exhibited significant proliferative effects on HMEC-1 cells. In the figure, * indicates promotion (P < 0.05); ** indicates promotion (P < 0.01).

[0425] Example 8: Effect of peptides on RSC96 cell proliferation

[0426] The concentration of glial cells (RSC96 cells) was adjusted to 1.0 × 10⁻⁶. 5 ~5.0×10 5 Cells were passaged at 37°C and 5% CO2 for 24–36 hours for biological activity assay. Cells were then digested with trypsin and collected, and reconstituted into serum-free medium at a concentration of 5 × 10⁻⁶ m³ / mL. 4 100 μL of the cells were seeded into 96-well cell culture plates, i.e., 5000 cells / well, and cultured overnight at 37°C and 5% CO2.

[0427] The polypeptide compounds of the present invention were prepared into test concentrations (0.2ug / ml, 0.4ug / ml, 0.8ug / ml) using 0% serum culture medium as experimental groups. An equal volume of 0% serum-free culture medium was added to the control group. The mixture was added in 4 replicates and incubated at 37°C and 5% CO2 for 48 hours.

[0428] Cell proliferation was detected using CCK-8: the old culture medium was removed, and serum-free culture medium containing 10% CCK-8 was added to each well. After incubation in an incubator for 2 hours, the absorbance was measured at 450 nm using an ELISA reader.

[0429] The test results are as follows Figures 33 to 40 As shown, peptide compounds 74, 68, 66, 1, and 64 all exhibited significant proliferative effects on RSC96 cells. In the figure, * indicates P < 0.05 compared to the control group; ** indicates P < 0.01 compared to the control group.

[0430] Although the present invention has disclosed the above embodiments, the implementation of the present invention is not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, or simplifications that do not depart from the present invention should be considered as equivalent substitutions and are included within the protection scope of the present invention. sequence list <110> Sichuan Good Doctor Panxi Pharmaceutical Co., Ltd. <120> A class of peptides for repairing skin or mucous membrane damage and their applications <130> F21W1046 <141> 2021-11-30 <150> CN 202110029899.X <151> 2021-01-11 <160> 73 <170> SIPOSequenceListing 1.0 <210> 1 <211> 15 <212> PRT <213> Artificial Sequence <400> 1 Ser Met Gln Ala Ser Leu Glu Ala Glu Ala Lys Gly Lys Ala Glu 1 5 10 15 <210> 2 <211> 13 <212> PRT <213> Artificial Sequence <400> 2 Gln Ala Ser Leu Glu Ala Glu Ala Lys Gly Lys Ala Glu 1 5 10 <210> 3 <211> 13 <212> PRT <213> Artificial Sequence <400> 3 Ser Met Gln Ala Ser Leu Glu Ala Glu Ala Lys Gly Lys 1 5 10 <210> 4 <211> 11 <212> PRT <213> Artificial Sequence <400> 4 Gln Ala Ser Leu Glu Ala Glu Ala Lys Gly Lys 1 5 10 <210> 5 <211> 11 <212> PRT <213> Artificial Sequence <400> 5 Ser Met Gln Ala Ser Leu Glu Ala Glu Ala Lys 1 5 10 <210> 6 <211> 9 <212> PRT <213> Artificial Sequence <400> 6 Gln Ala Ser Leu Glu Ala Glu Ala Lys 1 5 <210> 7 <211> 9 <212> PRT <213> Artificial Sequence <400> 7 Glu Ala Glu Ala Lys Gly Lys Ala Glu 1 5 <210> 8 <211> 6 <212> PRT <213> Artificial Sequence <400> 8 Ser Met Gln Ala Ser Leu 1 5 <210> 9 <211> 4 <212> PRT <213> Artificial Sequence <400> 9 Gln Ala Ser Leu 1 <210> 10 <211> 4 <212> PRT <213> Artificial Sequence <400> 10 Gly Lys Ala Glu 1 <210> 11 <211> 15 <212> PRT <213> Artificial Sequence <400> 11 Ser Met Gln Ala Ser Leu Glu Ala Glu Ala Lys Gly Lys Ala Glu 1 5 10 15 <210> 12 <211> 15 <212> PRT <213> Artificial Sequence <400> 12 Ser Val Gln Ala Ser Leu Glu Ala Glu Ala Lys Gly Lys Ala Glu 1 5 10 15 <210> 13 <211> 15 <212> PRT <213> Artificial Sequence <400> 13 Ser Met Gln Ala Ser Leu Glu Ala Glu Ala Lys Gly Lys Ala Gln 1 5 10 15 <210> 14 <211> 15 <212> PRT <213> Artificial Sequence <400> 14 Ser Met Gln Ala Ser Leu Gln Ala Gln Ala Lys Gly Lys Ala Glu 1 5 10 15 <210> 15 <211> 15[[ID=3D]] <212> PRT <213> Artificial Sequence <400> 15 Ser Met Gln Ala Ser Ala Glu Ala Glu Ala Lys Gly Lys Ala Glu 1 5 10 15 <210> 16 <211> 15 <212> PRT <213> Artificial Sequence <400> 16 Ser Ala Gln Ala Ser Leu Glu Ala Glu Ala Lys Gly Lys Ala Glu 1 5 10 15 <210> 17 <211> 15 <212> PRT <213> Artificial Sequence <400> 17 Ser Leu Gln Ala Ser Leu Glu Ala Glu Ala Lys Gly Lys Ala Glu 1 5 10 15 <210> 18 <211> 15 <212> PRT [[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​<213> Artificial Sequence <400> twenty one Ser Met Ala Ala Ser Leu Glu Ala Glu Ala Lys Gly Lys Ala Glu 1 5 10 15 <210> twenty two <211> 15 <212> PRT <213> Artificial Sequence <400> twenty two Ser Ile Gln Ala Ser Leu Glu Ala Glu Ala Lys Gly Lys Ala Glu 1 5 10 15 <210> twenty three <211> 15 <212> PRT <213> Artificial Sequence <400> twenty three Ser Met Gln Ala Ser Leu Glu Ala Glu Ala Lys Gly Lys Ala Asp 1 5 10 15 <210> twenty four <211> 15 <212> PRT <213> Artificial Sequence <400> twenty four Ser Met Gln Ala Ser Leu Glu Ala Glu Ala Lys Gly Lys Ala Asn 1 5 10 15 <210> 25 <211> 15 <212> PRT <213> Artificial Sequence <400> 25 Ser Met Gln Ala Ser Leu Glu Ala Glu Ala Lys Gly Arg Ala Glu 1 5 10 15 <210> 26 <211> 15 <212> PRT <213> Artificial Sequence <400> 26 Ser Met Gln Ala Ser Leu Glu Ala Glu Ala Lys Gly Ala Ala Glu 1 5 10 15 <210> 27 <211> 15 <212> PRT <213> Artificial Sequence <400> 27 Ser Met Gln Ala Ser Leu Glu Ala Glu Ala Lys Gly Lys Ala Ala 1 5 10 15 <210> 28 <211> 15 <212> PRT <213> Artificial Sequence[[ID=३9]] <400> 28 Ser Met Gln Ala Ala Leu Glu Ala Glu Ala Lys Gly Lys Ala Glu 1 5 10 15 <210> 29 <211> 15 <212> PRT <213> Artificial Sequence <400> 29 Ala Met Gln Ala Ser Leu Glu Ala Glu Ala Lys Gly Lys Ala Glu 1 5 10 15 <210> 30 <211> 15 <212> PRT <213> Artificial Sequence <400> 30 Ser Met Gln Ala Ser Leu Glu Ala Glu Ala Arg Gly Lys Ala Glu 1 5 10 15 <210> 31 <211> 15 <212> PRT <213> Artificial Sequence <400> 31 Ser Met Gln Ala Ser Leu Glu Ala Glu Ala Lys Gly His Ala Glu 1 5 10 15 <210> 32 <211> 15 <212> PRT <213> Artificial Sequence <400> 32 Ser Met Gln Ala Ser Leu Glu Ala Glu Ala His Gly Lys Ala Glu 1 5 10 15 <210> 33 <211> 15 <212> PRT <213> Artificial Sequence <400> 33 Ser Met Gln Ala Ser Leu Leu Ala Glu Ala Lys Gly Lys Ala Glu 1 5 10 15 <210> 34 <211> 15 <212> PRT <213> Artificial Sequence <400> 34 Ser Met Gln Ala Ser Leu Glu Ala Leu Ala Lys Gly Lys Ala Glu 1 5 10 15 <210> 35 <211> 15 <212> PRT <213> Artificial Sequence <400> 35 Ser Met Gln Ala Ser Leu Gln Ala Glu Ala Lys Gly Lys Ala Glu 1 5 10 15 <210> 36 <211> 15 <212> PRT <213> Artificial Sequence <400> 36 Ser Met Gln Ala Ser Leu Glu Ala Gln Ala Lys Gly Lys Ala Glu 1 5 10 15 <210> 37 <211> 15 <212> PRT <213> Artificial Sequence <400> 37 Ser Met Glu Ala Ser Leu Glu Ala Glu Ala Lys Gly Lys Ala Glu 1 5 10 15 <210> 38 <211> 15 <212> PRT <213> Artificial Sequence <400> 38 [[ID=​​​<210> 39 <211> 15 <212> PRT <213> Artificial Sequence <400> 39 Ser Met Gln Ala Ser Leu Glu Ala Asp Ala Lys Gly Lys Ala Glu 1 5 10 15 <210> 40 <211> 15 <212> PRT <213> Artificial Sequence <400> 40 Thr Met Gln Ala Ser Leu Glu Ala Glu Ala Lys Gly Lys Ala Glu 1 5 10 15 <210> 41 <211> 15 <212> PRT <213> Artificial Sequence <400> 41 Ser Met Gln Ala Thr Leu Glu Ala Glu Ala Lys Gly Lys Ala Glu 1 5 10 15 <210> 42 <211> 15 <212> PRT <213> Artificial Sequence <400> 42 Ser Met Gln Ala Ser Val Glu Ala Glu Ala Lys Gly Lys Ala Glu 1 5 10 15 <210> 43 <211> 15 <212> PRT <213> Artificial Sequence <400> 43 Ser Met Gln Ala Ser Leu Glu Ser Glu Ala Lys Gly Lys Ala Glu 1 5 10 15 <210> 44 <211> 15 <212> PRT <213> Artificial Sequence <400> 44 Ser Met Gln Ala Ser Leu Glu Ala Glu Ser Lys Gly Lys Ala Glu 1 5 10 15 <210> 45 <211> 4 <212> PRT <213> Artificial Sequence <400> 45 Glu Ala Glu Ala 1 <210> 46 <211> 7 <212> PRT <213> Artificial Sequence <400> 46 Glu Ala Glu Ala Lys Gly Lys 1 5 <210> 47 <211> 14 <212> PRT <213> Artificial Sequence <400> 47 Thr Ala Ser Thr Leu Glu Ala Glu Ala Lys Gly Lys Ala Glu 1 5 10 <210> 48 <211> 15 <212> PRT <213> Artificial Sequence <400> 48 Ser Thr Gln Ala Ser Leu Glu Ala Glu Ala Lys Gly Lys Ala Glu 1 5 10 15 <210> 49 <211> 16 <212> PRT <213> Artificial Sequence <400> 49 Ser Met Gln Ala Ser Leu Glu Ala Glu Ala Lys Gly Lys Ala Gln Asp 1 5 10 15 <210> 50 <211> 16 <212> PRT <213> Artificial Sequence <400> 50 Ser Met Gln Ala Ser Leu Glu Ala Glu Ala Lys Gly Lys Ala Gln Glu 1 5 10 15 <210> 51 <211> 16 <212> PRT <213> Artificial Sequence <400> 51 Ser Met Gln Ala Ser Leu Glu Ala Glu Ala Lys Gly Lys Ala Glu Leu 1 5 10 15 <210> 52 <211> 16 <212> PRT <213> Artificial Sequence <400> 52 Ser Met Gln Ala Ser Leu Glu Ala Glu Ala Lys Gly Lys Ala Glu Ala 1 5 10 15 <210> 53 <211> 17 <212> PRT <213> Artificial Sequence <400> 53 Ser Met Gln Ala Ser Leu Glu Ala Glu Ala Lys Gly Lys Ala Lys Gln 1 5 10 15 Asp <210> 54 <211> 15 <212> PRT <213> Artificial Sequence <400> 54 Ala Glu Pro Val Pro Leu Glu Ala Glu Ala Lys Gly Lys Ala Glu<00​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ 1 5 10 15 <210> 57 <211> 15 <212> PRT <213> Artificial Sequence <400> 57 Ser Met Gln Ala Ser Leu Glu Ala Glu Ala Lys Pro Lys Ala Glu 1 5 10 15 <210> 58 <211> 17 <212> PRT <213> Artificial Sequence <400> 58 Ser Met Gln Ala Ser Leu Glu Ala Glu Ala Lys Gly Lys Ala Lys Gln 1 5 10 15 Glu <210> 59 <211> 14 <212> PRT <213> Artificial Sequence <400> 59 Arg Lys Asp Val Tyr Glu Ala Glu Ala Lys Gly Lys Ala Glu 1 5 10 <210> 60 <211> 15 <212> PRT <213> Artificial Sequence <400> 60 Ser Met Gln Ala Ser Leu Glu Ala Glu Ala Lys Gly Lys Ser Glu 1 5 10 15 <210> 61 <211> 9 <212> PRT <213> Artificial Sequence <400> 61 Glu Ala Glu Ala Ala Gly Lys Ala Glu 1 5 <210> 62 <211> 14 <212> PRT <213> Artificial Sequence <400> 62 Phe Asp Ala Leu Lys Gln Gln Phe Gln Ala Phe Gln Leu Glu 1 5 10 <210> 63 <211> 14 <212> PRT <213> Artificial Sequence <400> 63 His Cys Leu Ala Gly Leu Lys Lys Asp Leu Glu Asp Leu Glu 1 5 10 <210> 64 <211> 13 <212> PRT <213> Artificial Sequence <400> 64 Glu Ile Asn Gln Leu Glu Leu Ile Lys Gln Ala Ser Ile 1 5 10 <210> 65 <211> 11 <212> PRT <213> Artificial Sequence <400> 65 Ala Ala Arg Leu Ala Asp Glu Leu Arg Ala Glu 1 5 10 <210> 66 <211> 9 <212> PRT <213> Artificial Sequence <400> 66 Glu Thr Leu Gln Arg Lys Asn Lys Glu 1 5 <210> 67 <211> 10 <212> PRT <213> Artificial Sequence <400> 67 Val Asp Ala Ala Val Leu Glu Lys Leu Glu 1 5 10 <210> 68 <211> 8 <212> PRT <213> Artificial Sequence <400> 68 Ala Ala Val Leu Asp Lys Leu Glu 1 5 <210> 69 <211> 8 <212> PRT <213> Artificial Sequence <400> 69 Ala Ala Val Leu Glu Lys Leu Glu 1 5 <210> 70 <211> 28 <212> PRT <213> Artificial Sequence <400> 70 Lys Phe Tyr Ser Gln Ser Thr Ala Ser Ser Ser Tyr Ala Tyr Pro Ser 1 5 10 15 His Phe Gly Pro Ala Gly Phe Ser Gly Ser His Ser 20 25 <210> 71 <211> 10 <212> PRT <213> Artificial Sequence <400> 71 Val Asp Ala Ala Val Ile Glu Lys Ile Glu 1 5 10 <210> 72 <211> 10 <212> PRT <213> Artificial Sequence <400> 72 Val Asp Ala Ala Met Val Leu Leu Thr Arg 1 5 10 <210> 73 <211> 10 <212> PRT <213> Artificial Sequence <400> 73 Val Asp Ala Ala Val Leu Met Leu Arg Thr 1 5 10

Claims

1. A compound or a physiologically compatible salt thereof, wherein the compound is selected from: Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu; Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu-Leu; Ser-Met-Gln-Ala-Ser-Leu-Glu-Ala-Glu-Ala-Lys-Gly-Lys-Ala-Glu-Ala.

2. Use of the compound of claim 1 or a physiologically compatible salt thereof in the preparation of a medicament for repairing gastric ulcers.

3. Use of the compound of claim 1 or a physiologically compatible salt thereof in the preparation of a medicament for repairing skin wounds.

4. The use of claim 3, wherein the skin trauma is related to diseases such as epidermal inflammation, mechanical and surgical wounds, burns and scalds, ulcers, fistulas, bedsores, and skin damage caused by radiotherapy and chemotherapy.

5. Use of the compound of claim 1 or a physiologically compatible salt thereof in the preparation of a medicament for treating chronic atrophic gastritis.

6. A pharmaceutical composition comprising the compound of claim 1 or a physiologically compatible salt thereof and a physiologically acceptable carrier.

7. A daily chemical composition comprising the compound of claim 1 or a physiologically compatible salt thereof and a physiologically acceptable carrier.

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