Polypeptide compound, preparation method therefor and use thereof

Abstract

Provided in the present invention are a polypeptide compound, a preparation method therefor and the use thereof. The targeting peptide of the present invention is a linear peptide or cyclic peptide containing non-natural chemical modification, which can improve the affinity between the targeting peptide and Sortilin protein and prolong the plasma half-life.

Description

Polypeptide compound and preparation method and application thereof

[0001] The present disclosure claims the priority of the Chinese patent application with the title of "Polypeptide compound and preparation method and application thereof", the application number of 2024110095887, which was filed on July 25, 2024 with the Chinese Patent Office, and the entire content of the above application is incorporated herein by reference. TECHNICAL FIELD

[0002] The present application relates to the technical field of biological medicine, in particular to a polypeptide compound and a preparation method and application thereof. BACKGROUND

[0003] Sortilin is a type I transmembrane multiligand receptor encoded by the SORT1 gene on chromosome 1p13, belonging to the Vacuolar sorting protein 10 protein (Vps10p) domain family (Hermey G, et al., Cell. Mol. Life Sci. 2009, 66(16): 2677-2689). Sortilin is also known as Neurotensin receptor 3 (NTSR3), with a molecular weight of 95 kDa. It was first discovered in human brain tissue and is mainly expressed in neurons, hepatocytes, adipocytes and leukocytes including macrophages (AI-Yozbaki M, et al., Biochim. Biophys. Acta Rev. Cancer 2020, 1874(2): 188429). The three-dimensional structure of Sortilin protein is composed of Vps10p domain, transmembrane helix and cytoplasmic tail, which are essential for endoplasmic reticulum transport (Yabe-Wade T, et al. FEBS Lett. 2018, 592(15): 2647-2657). Sortilin precursor is synthesized in the endoplasmic reticulum and processed into mature body in the trans-Golgi network, so most of Sortilin is located in the Golgi body, which plays its biological function as a lysosomal sorting receptor, and a small part of Sortilin is located on the cell membrane, which controls the transport of transmembrane proteins through receptor-mediated endocytosis (Ouyang S, et al., J. Cell. Physiol. 2020, 235(12): 8959-8971).

[0004] A growing body of evidence suggests that Sortilin is a protein factor closely related to lipid metabolism (Conlon DM, et al. Curr. Opin. Lipidol. 2019, 30(3): 198-204; Zhong LY, et al. Clin. Chim. Acta 2016, 460: 11-17). At the genetic level, genome-wide association analysis of the SORT1 gene in the human population identified a variety of common single nucleotide polymorphisms, and long-term epidemiological studies showed a strong correlation between plasma lipid levels and the SORT1 gene (Willer CJ, et al. Nat. Genet. 2013, 45(11): 1274-1283). At the protein level, Sortilin is widely expressed in cells closely related to lipid metabolism, such as macrophages, hepatocytes, and adipocytes (Gao A, et al., DNA Cell. Biol. 2017, 36(12): 1050-1061). Sortilin is involved in a variety of biological processes of lipid metabolism and is significantly associated with lipid disorders. On the cell membrane, Sortilin is mainly involved in receptor-mediated endocytosis and mediates the uptake of natural low-density lipoprotein by macrophages as an uptake receptor (Wong I, et al. Brain Behav. Immun. 2020, 24(4): 585-597). Intracellularly, Sortilin acts as a transport protein between the Golgi apparatus, endosomes, lysosomes, and cell membranes, mediating the transport of different ligands, such as lipoprotein lipase, apolipoprotein E, apolipoprotein A5, and apolipoprotein B100, etc. (Zollo A et al. Neural. Plast. 2017, 2017: 1892612).

[0005] In recent years, there is evidence that Sortilin is closely related to the proliferation, migration and invasion of cancer cells. Sortilin is significantly highly expressed in various cancers, such as breast cancer, endometrial cancer, cervical cancer, pancreatic cancer, colorectal cancer and skin cancer (Dal Farra C, et al. Int. J. Cancer 2001, 92(4): 503-509; Giorgi RR, et al., J. Neuroendocrinol. 2008, 20(9): 1052-1057; Truzzi F, et al., J. Invest. Dermatol. 2008, 128(8): 2031-2040; Xiong J, et al., Neuro. Oncol. 2013, 15(8): 990-1007; Gao F, et al. Am. J. Pathol. 2020, 190: 1931-1942). Due to the transport and endocytosis functions of Sortilin and its specific high expression in tumor tissues, Sortilin can be used as a target for polypeptide conjugate drugs and antibody conjugate drugs. The known Sortilin binding polypeptides are mostly obtained from neurotrophic factors (such as Neurotensin (NT), proNGF and proBDNF, etc.), but their affinity and metabolic stability with Sortilin are poor, making it difficult to be used for the development of polypeptide conjugate drugs (Quistgaard EM, et al., Nat. Struct. Mol. Biol. 2009, 16(1): 96-98; Andersen OS, et al., J. Biol. Chem. 2010, 285(16): 12210-12222; Skeldal S, et al. J. Biol. Chem. 2012, 287(52): 43798-43809). The polypeptide TH19P01 developed by Theratechnologies Inc. is the only polypeptide used in the clinical stage polypeptide conjugate drug targeting Sortilin, but its affinity Kd value for Sortilin is between micromolar and hundreds of nanomolar, which needs to be improved (Demeule M, et al., Cancer Sci. 2021, 12: 4317-4334; Charfi C, et al., Front. Oncol. 2021, 11: 760787).

[0006] In summary, the development of novel Sortilin binding polypeptides with high affinity and high metabolic stability has become an urgent problem to be solved for the development of polypeptide conjugate drugs targeting Sortilin. SUMMARY

[0007] The object of the present application is to provide a targeting peptide against a target protein Sortilin having high affinity and long half-life in plasma.

[0008] Solution for solving the problem

[0009] In a first aspect, the present application provides an isolated peptide compound or a derivative thereof or a pharmaceutically acceptable salt thereof, comprising:

[0010] (i) an amino acid sequence comprising the amino acid sequence represented by Formula (I):

[0011] R1-X1-P1-X2-P2-X3-P3-X4-P4-X5-P5-P6-B1 Formula (I); or

[0012] (ii) an amino acid sequence having at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% sequence identity to the amino acid represented by Formula (I), and which retains the activity of the amino acid sequence represented by Formula (I);

[0013] wherein,

[0014] R1 is a modification group of N-terminal amino group or is absent;

[0015] X1, X2, X3, X4, X5 are independently selected from natural amino acid, unnatural amino acid, chemical modification of natural or unnatural amino acid, or a combination thereof;

[0016] P1 is selected from any one of Asn, Glu, Cys, Sec, Arg, Lys, His, Cit, Orn, Dab, Aha, Thea, Dimk, Isorn, 3AmiPhe, 4AmiPhe, 3GuPhe, 4GuPhe, hCys, hArg, AcLys, MeArg, MeLys, IPegDab and SPegDab;

[0017] P2 is selected from any one of Ala, Gly, lie, Val, Leu, Pro, Nle, Sar, tBuA, Dpr, A2Bu, Dbu, Abu, Aib, OctG, PipAla, PyrrAla, BnG, Cha, Cpa, C4al, C5al, Thea, MeAla, MeGly, MeIle, MeVal, MeLeu, MeNle, 4-AmPyrrl, 4-AmPyrr2, 4-PhePyrrl, 4-PhePyrr2, 5-PhePyrrl, 5-PhePyrr2, HyPro, Pip, Pzp, Ampc, Cpa, MeAla, MeGly, MeIle, MeVal, MeLeu, MeNle, hCha and 4-PryAla;

[0018] P3 is selected from any one of Asn, Gin, Trp, Arg, Lys, His, Cit, Orn, 2AmPhe, 3AmPhe, 4AmPhe, 3AmiPhe, 4AmiPhe, 3GuPhe, 4GuPhe, Cha, C4al, C5al, Thi, Tza, Mso, Aha, 4-AmPyrrl, 4-AmPyrr2, 4-PhePyrrl, 4-PhePyrr2, 5-PhePyrrl, 5-PhePyrr2, HyPro, Pip, Pzp, Ampc, Cpa, MeArg, hCha, hArg and 4-PryAla;

[0019] P4 is selected from any one of Lys, Arg, His, Gin, Pro, Dab, Cit, Orn, Thi, Tza, Aha, Aoc, HyPro, hArg, 3AmiPhe, 4AmiPhe, Dimk, AcLys, MeLys, MeArg, Pip, Pzp, IPegDab and SPegDab;

[0020] P5 is selected from any one of Phe, Tyr, Trp, His, 1-Nal, Thi, 2-Nal, 2AmPhe, 3AmPhe, 4AmPhe, 3AmiPhe, 4AmiPhe, 3GuPhe, 4GuPhe, 4-AmPyrrl, 4-AmPyrr2, 4-PhePyrrl, 4-PhePyrr2, 5-PhePyrrl, 5-PhePyrr2, 2Cl-Phe, 3Cl-Phe, 4Cl-Phe, 3,4Cl2-Phe, 3F-Phe, 4F-Phe, 4GuPhe, Bip, BnG, Bpa, C4al, C5al, Cha, Cpa, Phg, Tza, yBzl, hCha, hPhe and MePhe;

[0021] P6 is selected from any one of Ala, Gly, Val, lie, Leu, Pro, Met, Nle, 4-AmPyrrl, 4-AmPyrr2, 4-PryAla, A2Bu, Abu, Aib, Cha, C4al, C5al, Dbu, Dpr, Pip, Pzp, Sar, tBuG, MeAla, MeGly, MeIle, MeLeu, MeVal, MeNle, hCha and Mso;

[0022] B1 is selected from any one of Val, lie, Leu, Nle, Aha, MeIle, MeLeu, MeVal and MeNle.

[0023] Preferably, P1 is Asn, Glu, Arg, Lys, Cit, Orn or Dab, more preferably Cit, Orn or Arg, most preferably Arg.

[0024] Preferably, P2 is Ala, Gly, lie, Val, Leu, Pro, Nle, Dbu, Aha or Dpr, more preferably Aha, Aib, Nle, lie, Val or Leu, most preferably Val.

[0025] Preferably, P3 is Asn, Gin, Arg, Lys or His, more preferably Asn or Gin, most preferably Gin.

[0026] Preferably, P4 is Lys, Arg, His, Dab, Dbu or Aha, more preferably Lys, Dab, Dbu or Aha, most preferably Lys.

[0027] Preferably, P5 is Phe, Tyr, Trp, His, Thi or Phg, more preferably Phe, Tyr, Trp and His, preferably Tyr.

[0028] Preferably, P6 is Ala, Gly, Val, lie, Leu, Pro, Nle, Abu, Aha or Aib, more preferably Abu, Aib, Val or lie, preferably lie.

[0029] Preferably, B1 is Val, lie, Leu, Nle, Aha, MeIle, MeLeu, MeVal or MeNle, more preferably Leu, Aha or Nle, most preferably Leu.

[0030] Preferably, X1is Ala, Gly, lie, Leu, Pro, Phe, Val, Tyr, Trp, Aib, Nle, Pip, Pzp, Sar, tBuG, or a combination thereof.

[0031] Preferably, X2is Aha, Dab, tBuG, Ala, Gly, lie, Lys, Cys, Sar, Leu, Val, or a combination thereof.

[0032] Preferably, X3is Cit, Orn, Cys, Arg, or a combination thereof.

[0033] Preferably, X4is Mso, Nle, Cys, Leu, Met, Phe, Tyr, Trp, or a combination thereof.

[0034] Preferably, X5is Pip, Pzp, Pro, or a combination thereof.

[0035] Preferably, the modification group of the N-terminal amino group is selected from Ac, Cbz, Boc, Fmoc, Alloc, Teoc, Pht, Tos, Tfa, Trt, Dmb, PMB, Bn, methoxycarbonyl, and ethoxycarbonyl.

[0036] Preferably, X1is 1-3 amino acid residues, preferably 2 amino acid residues, more preferably Pip-Phe, Pip-Tyr, Pip-Leu, Pip-Val, Pzp-Phe, Pzp-Tyr, Pzp-Leu, Pzp-Val, Sar-Ile, Sar-Leu, Sar-Val, tBuG-Ile, tBuG-Leu, tBuG-Val, Ala-Phe, Gly-Ile, Gly-Leu, Gly-Val, lie-Val, Leu-Phe, Pro-Aib, Pro-Ala, Pro-Phe, Pro-Leu, Pro-Val, Pro-Trp, Pro-Tyr, or Val-Phe, more preferably Ala-Phe, Gly-Val, Leu-Phe, lie-Val, Pro-Tyr, Val-Phe, Pro-Phe, or Pro-Ala.

[0037] Preferably, X2is 2 to 5 amino acid residues, preferably 4 amino acid residues, more preferably Aha-Ile-Gly-Ala, Dab-Ile-Gly-Ala, tBuG-Lys-Ala-Sar, Ala-Aha-Leu-Ile, Ala-Aha-Ala-Gly, Ala-Dab-Ala-Gly, Ala-Dab-Leu-Ile, Ala-Lys-Leu-Ile, Ala-Lys-Ala-Sar, Ala-Lys-Ala-Gly, Ala-Lys-Val-Leu, Gly-Aha-Ala-Gly, Gly-Dab-Ala-Gly, Gly-Lys-Ala-Gly, Gly-Lys-Val-Leu, Ile-Aha-Ala-Gly, Ile-Aha-Leu-Ile, Ile-Dab-Ala-Gly, Ile-Dab-Ala-Sar, Ile-Dab-Gly-Ala, Ile-Dab-Leu-Ile, Ile-Cys-Gly-Ala, Ile-Cys-Ala-Gly, Ile-Cys-Sar-Ala, Ile-Cys-Ala-tBuG, Ile-Cys-Leu-Ile, Ile-Lys-Leu-Ile, Ile-Lys-Sar-Ala, Ile-Lys-Ala-Gly, Ile-Lys-Ala-Sar, Ile-Lys-Gly-Ala, Lys-Ile-Gly-Ala or Lys-Ile-tBuG-Ala, most preferably Ala-Lys-Leu-Ile, Ala-Lys-Ala-Gly, Ala-Lys-Val-Leu, Gly-Lys-Ala-Gly, Gly-Lys-Val-Leu, Ile-Lys-Gly-Ala, Ile-Cys-Gly-Ala or Ile-Lys-Ala-Gly.

[0038] Preferably, X3is 1 to 2 amino acid residues, preferably 1 amino acid residue, more preferably Cit, Orn, Cys or Arg, most preferably Arg.

[0039] Preferably, X4is 1 to 3 amino acid residues, preferably 2 amino acid residues, more preferably Mso-Phe, Mso-Tyr, Mso-Trp, Nle-Phe, Nle-Tyr, Nle-Trp, Cys-Phe, Cys-Tyr, Cys-Trp, Leu-Phe, Leu-Tyr, Leu-Trp, Met-Phe, Me-Tyr or Met-Trp, most preferably Met-Phe, Met-Tyr or Met-Trp.

[0040] Preferably, X5is 1-2 amino acid residues, preferably 1 amino acid residue, more preferably Pip, Pzp or Pro, most preferably Pro.

[0041] Preferably, it comprises an amino acid sequence represented by formula (I-1): R1-X 1-1 -X 1-2 -P1-X 2-1 -X 2-2 -X 2-3 -X 2-4 -P2-X3-P3-X 4-1 -X 4-2 -P4-X5-P5-P6-B1 Formula (I-1),

[0042] wherein R1, P1, P2, P3, P4, P5, P6and B1are as defined in any of the above;

[0043] X 1-1 , X 1-2 , X 2-1 , X 2-2 , X 2-3 , X 2-4 , X3, X 4-1 , X 4-2 , X5is independently selected from natural amino acids, unnatural amino acids, chemical modifications of natural or unnatural amino acids.

[0044] Preferably, X 1-1 is Pip, Pzp, Sar, tBuG, Ala, Gly, Ile, Leu, Pro or Val, preferably Ala, Gly, Ile, Leu, Pro or Val.

[0045] Preferably, X 1-2 is Aib, Nle, Ala, Ile, Leu, Val, Tyr, Phe or Trp, preferably Ala, Phe, Ile, Val or Tyr.

[0046] Preferably, X 2-1 is Aha, Dab, tBuG, Ala, Gly, Ile or Lys, preferably Gly or Ile.

[0047] Preferably, X 2-2 is Cys, Ile, Aha, Dab or Lys, preferably Cys or Lys.

[0048] Preferably, X 2-3 is Sar, tBuG, Ala, Gly, Leu or Val, preferably Gly, Leu or Val.

[0049] Preferably, X 2-4 is Sar, tBuG, Ala, Gly, lie or Leu, preferably Ala, Gly, lie or Leu.

[0050] Preferably, X3is Cit, Orn, Cys or Arg, preferably Cys or Arg.

[0051] Preferably, X 4-1 is Mso, Nle, Cys, Leu or Met, preferably Cys or Met.

[0052] Preferably, X 4-2 is Phe, Tyr or Trp, preferably Phe or Tyr.

[0053] Preferably, X5is Pip, Pzp or Pro, preferably Pro.

[0054] Preferably, it comprises an amino acid sequence represented by formula (I-1-1): R1-X 1-1 -X 1-2 -Arg-X 2-1 -X 2-2 -X 2-3 -X 2-4 -Val-X3-P3-X 4-1 -X 4-2 -Lys-X5-Tyr-P6-Leu Formula (I-1-1),

[0055] wherein R1, X 1-1 , X 1-2 , X 2-1 , X 2-2 , X 2-3 , X 2-4 , X3, P3, X 4-1 , X 4-2 , P6, X5are as defined in any of the preceding items.

[0056] Preferably, the amino acid sequence of the peptide compound is selected from any one of SEQ ID NO. 1 to SEQ ID NO. 108.

[0057] Preferably, the peptide compound represented by formula (I) is a linear peptide.

[0058] In a second aspect, the present application provides an isolated peptide compound, or a derivative thereof, or a pharmaceutically acceptable salt thereof, comprising:

[0059] (i) comprising an amino acid sequence represented by formula (II):

[0060] R2-A1-P7-X6-P8-P9-X7-A2-X8-P 10 -B2 Formula (II); or

[0061] (ii) has at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% sequence identity to an amino acid sequence as shown in Formula (II) and retains the activity of the amino acid sequence as shown in Formula (II);

[0062] wherein,

[0063] R2is a modification group of the N-terminal amino group or is absent;

[0064] X6, X7, X8are independently selected from absent or from a natural amino acid, a non-natural amino acid, a chemical modification of a natural or non-natural amino acid, or a combination thereof;

[0065] A1and A2are each independently selected from any one of Cys, Sec, and Pen;

[0066] P7is selected from absent, Ser, Thr, Tyr, Trp, Cys, Thea, His, Sec, Pen, hSer, hCys, AlloT, sBzl, tBzl, and yBzl;

[0067] P8is selected from Asn, Glu, Cys, Sec, Pro, Arg, Lys, His, Cit, Orn, Dab, Aha, Thea, Dimk, Isorn, 3AmiPhe, 4AmiPhe, 3GuPhe, 4GuPhe, hCys, hArg, AcLys, MeArg, MeLys, IPegDab, and SPegDab;

[0068] P9is selected from Phe, Tyr, Trp, His, 1-Nal, 2-Nal, 2AmPhe, 3AmPhe, 4AmPhe, 3AmiPhe, 4AmiPhe, 3GuPhe, 4GuPhe, 4-AmPyrr1, 4-AmPyrr2, 4-PhePyrr1, 4-PhePyrr2, 5-PhePyrr1, 5-PhePyrr2, 2Cl-Phe, 3Cl-Phe, 4Cl-Phe, 3,4Cl2-Phe, 3F-Phe, 4F-Phe, 4GuPhe, Bip, BnG, Bpa, C4al, C5al, Cha, Cpa, Phg, Tza, yBzl, hCha, hPhe, MePhe, Thi, Pro, Arg, and Leu;

[0069] P 10 is selected from any one of Ala, Gly, Val, lie, Leu, Pro, Met, Nle, 4-AmPyrrl, 4-AmPyrr2, 4-PryAla, A2Bu, Abu, Aib, Cha, C4al, C5al, Dbu, Dpr, Pip, Pzp, Sar, tBuG, MeAla, MeGly, MeIle, MeLeu, MeVal, MeNle, hCha and Mso;

[0070] B2 is selected from any one of Val, lie, Leu, Trp, Nle, Aha, MeIle, MeLeu, MeVal and MeNle.

[0071] Preferably, A1 and A2 are each independently Cys or Pen, preferably Cys.

[0072] Preferably, P7 is Ser, Thr, Tyr, Trp, Cys, Thea, His, Sec, Pen or absent, more preferably Ser, Thr, Tyr, Trp, Thea or His, most preferably Thr.

[0073] Preferably, P8 is Asn, Glu, Cys, Pro, Arg, Lys, Cit, Orn, Dab or Aha, more preferably Arg, Cit or Orn, most preferably Arg.

[0074] Preferably, P9 is Phe, Tyr, Trp, His, Phg, Tza, Thi, Pro, Arg or Leu; more preferably Phe, Tyr, Trp or His, most preferably Tyr.

[0075] Preferably, P 10 is Ala, Gly, Val, lie, Leu, Pro, Nle, Abu or Aib; more preferably lie, Abu or Aib, most preferably lie.

[0076] Preferably, B2 is Leu, Trp, Nle or Aha; more preferably Leu, Trp or Nle, most preferably Leu.

[0077] Preferably, X6 is Lys, Aha, Cit, Orn, Dab, Glu, Asn, Pro, Arg, Trp, Ser, Gly, lie, Ala or a combination thereof.

[0078] Preferably, X7is absent, Abu, Aib, Dbu, Dpr, Sar, tBuG, Ala, Gly, Ile, Leu, Pro, Arg, Val or combinations thereof.

[0079] Preferably, X8is absent or is Tyr, more preferably absent.

[0080] Preferably, the modification group of the N-terminal amino group is selected from Ac, Cbz, Boc, Fmoc, Alloc, Teoc, Pht, Tos, Tfa, Trt, Dmb, PMB, Bn, methoxycarbonyl and ethoxycarbonyl.

[0081] Preferably, X6is 2 to 5 amino acid residues, preferably 3 to 5 amino acid residues, more preferably Aha-Ser-Aha, Aha-Ser-Cit, Aha-Ser-Orn, Aha-Ser-Lys, Aha-Ser-Asn, Cit-Ser-Aha, Cit-Ser-Lys, Dab-Ser-Cit, Dab-Ser-Dab, Dab-Ser-Orn, Dab-Ser-Lys, Dab-Ser-Asn, Dab-Ser-Arg, Orn-Ser-Aha, Orn-Ser-Lys, Glu-Ser-Glu, Glu-Ser-Ile, Gly-Ser-Lys, Gly-Ser-Ile, Lys-Ser-Gly, Lys-Ser-Ile, Lys-Lys-Ile, Lys-Ser-Lys, Lys-Ser-Asn, Lys-Ser-Arg, Lys-Ser-Aha, Lys-Ser-Cit, Lys-Ser-Dab, Lys-Ser-Orn, Asn-Ser-Aha, Asn-Ser-Dab, Asn-Ser-Lys, Pro-Ser-Lys, Arg-Ser-Lys, Arg-Lys-Lys, Ser-Lys-Ile, Trp-Ser-Ile, Trp-Lys-Lys, Arg-Lys-Ala-Lys or Arg-Lys-Pro-Lys-Pro, most preferably Gly-Ser-Lys, Lys-Ser-Lys, Arg-Lys-Lys, Trp-Lys-Lys, Pro-Ser-Lys, Arg-Lys-Ala-Lys or Arg-Lys-Pro-Lys-Pro.

[0082] Preferably, X7is absent or 1-2 amino acid residues, preferably 1 amino acid residue, more preferably Abu, Aib, Dbu, Dpr, Sar, tBuG, Ala, Gly, lie, Leu, Pro, Arg or Val, most preferably lie.

[0083] Preferably, it comprises an amino acid sequence represented by formula (II-1): R2-A1-P7-X 6-1 -X 6-2 -X 6-3 -X 6-4 -X 6-5 -P8-P9-X7-A2-X8-P 10 -B2 formula (II-1),

[0084] wherein R2, A1, P7, P8, P9, X7, A2, X8, P 10 , B2 are as defined in any of the preceding items;

[0085] X 6-1 , X 6-2 , X 6-3 , X 6-4 , X 6-5 is independently selected from absent or from a natural amino acid, an unnatural amino acid, a chemical modification of a natural or unnatural amino acid.

[0086] Preferably, X 6-1 is Aha, Cit, Dab, Orn, Glu, Gly, Lys, Asn, Pro, Arg, Ser or Trp, more preferably Lys, Arg or Trp, most preferably Lys or Arg.

[0087] Preferably, X 6-2 is Ser or Lys, more preferably Ser.

[0088] Preferably, X 6-3 is absent, Pro or Ala, more preferably Pro or Ala.

[0089] Preferably, X 6-4 is Aha, Cit, Dab, Orn, Glu, Gly, lie, Lys, Asn or Arg; more preferably lie or Lys, most preferably Lys.

[0090] Preferably, X 6-5 is absent or Pro.

[0091] Preferably, it comprises an amino acid sequence represented by formula (II-1-1): R2-Cys-P7-X 6-1 -Ser-X 6-3 -X6-4 -X 6-5 -P8-P9-X7-Cys-Ile-B2 Formula (II-1-1),

[0092] wherein, R2, P7, X 6-1 , X 6-3 , X 6-4 , X 6-5 , P8, P9, X7, B2 are defined as any one of the above.

[0093] Preferably, the peptide compound represented by Formula (II) is a linear peptide or a cyclic peptide, preferably a cyclic peptide.

[0094] Preferably, the amino acid at position A1 and the amino acid at position A2 form a covalent bond to form a cyclic peptide.

[0095] More preferably, the amino acid at position A1 and the amino acid at position A2 form a disulfide bond or a diselenide bond to form a cyclic peptide.

[0096] Preferably, the amino acid sequence of the peptide compound is selected from any one of SEQ ID NO. 109 to SEQ ID NO. 234.

[0097] In a third aspect, the present application provides a drug conjugate or a pharmaceutically acceptable salt thereof, the drug conjugate having a structure represented by Formula (III):

[0098] wherein, a is an integer from 0 to 10;

[0099] E is a peptide compound or a derivative thereof or a pharmaceutically acceptable salt thereof as any one of the above;

[0100] A is a cytotoxic agent;

[0101] L is a linker connecting E and A, and the wavy line in Formula (III) indicates that L is covalently connected to a side chain residue or a terminal group of E.

[0102] In a fourth aspect, the present application provides a pharmaceutical composition comprising the peptide compound or a derivative thereof or a pharmaceutically acceptable salt thereof of any one of the first aspect and the second aspect, or the drug conjugate or a pharmaceutically acceptable salt thereof of the third aspect, and a pharmaceutically acceptable carrier and / or excipient.

[0103] In a fifth aspect, the present application provides the use of the peptide compound or a derivative thereof or a pharmaceutically acceptable salt thereof of any one of the first aspect and the second aspect, or the drug conjugate or a pharmaceutically acceptable salt thereof of the third aspect, or the pharmaceutical composition of the fourth aspect, in the preparation of a medicament for the prevention and treatment of tumors / cancers.

[0104] Preferably, the tumor / cancer overexpresses Sortilin.

[0105] In a sixth aspect, the present application provides a method for treating a tumor and / or a cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the peptide compound of any one of the above, or the drug conjugate of the above, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the above.

[0106] Effects of the application

[0107] The targeting peptide provided by the present application has high affinity to SORT1 protein, high metabolic stability and specific targeting to Sortilin. Meanwhile, the targeting peptide provided by the present application has a long plasma half-life, good pharmacokinetics and pharmacodynamics characteristics. BRIEF DESCRIPTION OF DRAWINGS

[0108] Figure 1 is a structural schematic diagram of the binding of the polypeptide to Sortilin. In the figure, the protein skeleton structure of Sortilin is represented by Ribbon, and the skeleton structure of the polypeptide is represented by space-filling;

[0109] Figure 2 is a schematic diagram of the SPR affinity detection results of Neurotensin and Sortilin at different concentrations. The curves from top to bottom in the figure represent the RU values of Neurotensin at concentrations of 500nM, 250nM, 125nM, 62.5nM, 31.25nM and 15.63nM, respectively;

[0110] Figure 3 is a schematic diagram of the SPR affinity detection results of TH19P01 and Sortilin at different concentrations. The curves from top to bottom in the figure represent the RU values of TH19P01 at concentrations of 500nM, 250nM, 125nM, 62.5nM, 31.25nM and 15.63nM, respectively;

[0111] Figure 4 is a schematic diagram of the SPR affinity detection results of the polypeptide SEQ ID NO. 92 and Sortilin at different concentrations. The curves from top to bottom in the figure represent the RU values of the peptide compound represented by SEQ ID NO. 92 at concentrations of 500nM, 250nM, 125nM, 62.5nM and 31.25nM, respectively;

[0112] Figure 5 is a schematic diagram of the SPR affinity detection results of the polypeptide SEQ ID NO. 231 and Sortilin at different concentrations. The curves from top to bottom in the figure represent the RU values of the peptide compound represented by SEQ ID NO. 231 at concentrations of 500nM, 250nM, 125nM, 62.5nM and 31.25nM, respectively. DETAILED DESCRIPTION

[0113] In order to make the technical solutions and beneficial effects of the present application more apparent and understandable, specific embodiments will be described in detail below. The drawings are not necessarily drawn to scale, and local features can be enlarged or reduced to more clearly show the details of the local features.

[0114] In order to make the technical solutions and beneficial effects of the present application more apparent and understandable, specific embodiments will be described in detail below. The drawings are not necessarily drawn to scale, and local features can be enlarged or reduced to more clearly show the details of the local features.

[0115] As used herein, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise.

[0116] As used herein, the terms "SORT1 protein", "Sortilin" are used interchangeably and refer to the neuronal type 1 membrane glycoprotein encoded by the SORT1 gene (GeneID: 6272), belonging to the vacuolar protein sorting 10 protein (Vps10) receptor family.

[0117] As used herein, the terms "isolated polypeptide", "targeting peptide", "peptide compound" are used interchangeably and refer to the synthetic polypeptide compound of the present application targeting SORT1 protein.

[0118] Unless otherwise specified, all amino acids are used in the L-configuration.

[0119] The names and three-letter codes and one-letter codes of some common amino acids are shown in Table 1:

[0120] Table 1

[0121] As used herein, the term "amino acid" refers to naturally occurring and non-naturally occurring amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those modified after synthesis, such as hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acid analogs refer to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an α-carbon that is bonded to a hydrogen, a carboxyl group, an amino group, and an R group, such as homoserine, norleucine, methionine sulfoxide, methionine methylsulfonium. Such analogs can have modified R groups (e.g., norleucine) or modified peptide backbones, but otherwise function in a manner similar to naturally occurring amino acids. Amino acid mimetics refer to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid.

[0122] As used herein, the term "non-naturally occurring amino acid" is a compound that has the same basic chemical structure as a naturally occurring amino acid, but is not incorporated into a growing polypeptide chain by a translation complex. "Non-naturally occurring amino acids" also include, but are not limited to, amino acids that result from modification (e.g., post-translational modification) of a naturally encoded amino acid (including, but not limited to, the 20 common amino acids) that are not themselves naturally incorporated into a growing polypeptide chain by a translation complex. A non-limiting list of examples of non-naturally occurring amino acids that can be inserted into or substituted for wild-type residues in a polypeptide sequence include beta-amino acids, homoamino acids, cyclic amino acids, and amino acids with derivatized side chains.

[0123] As used herein in reference to peptides, "amino acid" and "amino acid residue" have the same meaning, referring to: when amino acids are connected by chemical bonds between them, the partial groups are lost due to the formation of the connecting bond, and the remaining amino acid part is the amino acid residue.

[0124] As used herein, the term "derivative" refers to a polypeptide that substantially maintains the function or activity of binding to Sortilin. It will be appreciated that amino acid derivatives of the peptide compounds as defined herein are within the scope of the present application. Examples of such suitable modified amino acid derivatives include one or more modifications selected from the group consisting of: N-terminal and / or C-terminal modifications; replacement of one or more amino acid residues with one or more non-natural amino acid residues (e.g., replacement of one or more polar amino acid residues with one or more isosteric or isoelectronic amino acids; replacement of one or more non-polar amino acid residues with other non-natural isosteric or isoelectronic amino acids); addition of a spacer group; replacement of one or more oxidation-sensitive amino acid residues with one or more oxidation-resistant amino acid residues; replacement of one or more amino acid residues with alanine, replacement of one or more L-amino acid residues with one or more D-amino acid residues; N-alkylation of one or more amide bonds in a bicyclic peptide ligand; replacement of one or more peptide bonds with surrogate bonds; peptide backbone length modification; substitution of the hydrogen on the alpha-carbon of one or more amino acid residues with another chemical group, modification of amino acids such as glycine, alanine, phenylalanine, cysteine, lysine, glutamate / aspartate, and tyrosine, etc. with suitable amine, thiol, carboxylic acid, and phenol reactive reagents to functionalize the amino acid, and introduction or replacement of amino acids to introduce orthogonal reactivity suitable for functionalization, for example, amino acids bearing an azide or alkyne group to allow functionalization with alkyne or azide bearing moieties, respectively. These derivatives or analogs are within the purview of one of skill in the art in light of the teachings herein.

[0125] As used herein, the terms "homology," "identity" indicate sequence similarity to a wild-type amino acid sequence or a wild-type nucleic acid sequence, and homology comparisons can be made by eye or using commercially available comparison programs. Using commercially available computer programs, homology between two or more sequences can be expressed as a percentage (%) and the homology (%) between adjacent sequences can be calculated.

[0126] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio, and effective for their intended use.

[0127] As used herein, the term "pharmaceutically acceptable salt" means a salt of a compound of the present application that retains the biological effectiveness and properties of the free acids or free bases and refers to the salt of the free acid form of the compound which is obtained by reaction with a non-toxic inorganic or organic base and the salt of the free base form of the compound which is obtained by reaction with a non-toxic inorganic or organic acid.

[0128] As used herein, the term "pharmaceutical composition" means a mixture of one or more compounds described herein or stereoisomers, solvates, pharmaceutically acceptable salts or co-crystals thereof, with other ingredients, wherein the other ingredients are pharmaceutically acceptable carriers and / or excipients.

[0129] As used herein, the term "solvate" means the physical association of one or more, preferably 1-3, solvent molecules with a compound of the present application, either organic or inorganic. This physical association includes hydrogen bonding. In certain instances, the solvate will be isolated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are well known in the art.

[0130] As used herein, "carrier" refers to a system that does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the administered compound, and can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug and deliver the drug to the target organ, non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0131] As used herein, "excipient" refers to a substance that is not itself a therapeutic agent, used as a diluent, adjuvant, binder, and / or vehicle, for addition to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate formation of a compound or pharmaceutical composition into a unit dosage form for administration. Pharmaceutical excipients can serve various functions and can be described as wetting agents, buffering agents, suspending agents, lubricating agents, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavorants, and sweeteners, as known to those skilled in the art. Examples of pharmaceutical excipients include, but are not limited to: (1) sugars, such as lactose, dextrose, and sucrose; (2) starches, such as corn starch and potato starch; (3) celluloses and their derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose, and crosscarmellose (e.g., crosscarmellose sodium); (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laureate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and / or polyanhydrides; and (22) other non-toxic compatible substances used in pharmaceutical formulations.

[0132] In a first aspect, the present application provides an isolated peptide compound or a derivative thereof or a pharmaceutically acceptable salt thereof, comprising:

[0133] (i) an amino acid sequence represented by Formula (I):

[0134] R1-X1-P1-X2-P2-X3-P3-X4-P4-X5-P5-P6-B1 Formula (I); or

[0135] (ii) an amino acid sequence having at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% sequence identity to the amino acid represented by Formula (I), and which retains the activity of the amino acid sequence represented by Formula (I);

[0136] wherein,

[0137] R1is a modification group of the N-terminal amino group or is absent;

[0138] Xi, X2, X3, X4, X5are independently selected from natural amino acids, unnatural amino acids, chemical modifications of natural or unnatural amino acids, or combinations thereof;

[0139] Pi is selected from any one of Asn, Glu, Cys, Sec, Arg, Lys, His, Cit, Orn, Dab, Aha, Thea, Dimk, Isorn, 3AmiPhe, 4AmiPhe, 3GuPhe, 4GuPhe, hCys, hArg, AcLys, MeArg, MeLys, IPegDab and SPegDab;

[0140] P2is selected from any one of Ala, Gly, lie, Val, Leu, Pro, Nle, Sar, tBuA, Dpr, A2Bu, Dbu, Abu, Aib, OctG, PipAla, PyrrAla, BnG, Cha, Cpa, C4al, C5al, Thea, MeAla, MeGly, MeIle, MeVal, MeLeu, MeNle, 4-AmPyrr1, 4-AmPyrr2, 4-PhePyrr1, 4-PhePyrr2, 5-PhePyrr1, 5-PhePyrr2, HyPro, Pip, Pzp, Ampc, Cpa, MeAla, MeGly, MeIle, MeVal, MeLeu, MeNle, hCha and 4-PryAla;

[0141] P3is selected from any one of Asn, Gin, Trp, Arg, Lys, His, Cit, Orn, 2AmPhe, 3AmPhe, 4AmPhe, 3AmiPhe, 4AmiPhe, 3GuPhe, 4GuPhe, Cha, C4al, C5al, Thi, Tza, Mso, Aha, 4-AmPyrr1, 4-AmPyrr2, 4-PhePyrr1, 4-PhePyrr2, 5-PhePyrr1, 5-PhePyrr2, HyPro, Pip, Pzp, Ampc, Cpa, MeArg, hCha, hArg and 4-PryAla;

[0142] P4is selected from any one of Lys, Arg, His, Gin, Pro, Dab, Cit, Orn, Thi, Tza, Aha, Aoc, HyPro, hArg, 3AmiPhe, 4AmiPhe, Dimk, AcLys, MeLys, MeArg, Pip, Pzp, IPegDab and SPegDab;

[0143] P5 is selected from any one of Phe, Tyr, Trp, His, 1-Nal, Thi, 2-Nal, 2AmPhe, 3AmPhe, 4AmPhe, 3AmiPhe, 4AmiPhe, 3GuPhe, 4GuPhe, 4-AmPyrrl, 4-AmPyrr2, 4-PhePyrrl, 4-PhePyrr2, 5-PhePyrrl, 5-PhePyrr2, 2Cl-Phe, 3Cl-Phe, 4Cl-Phe, 3,4Cl2-Phe, 3F-Phe, 4F-Phe, 4GuPhe, Bip, BnG, Bpa, C4al, C5al, Cha, Cpa, Phg, Tza, yBzl, hCha, hPhe, and MePhe;

[0144] P6 is selected from any one of Ala, Gly, Val, Ile, Leu, Pro, Met, Nle, 4-AmPyrrl, 4-AmPyrr2, 4-PryAla, A2Bu, Abu, Aib, Cha, C4al, C5al, Dbu, Dpr, Pip, Pzp, Sar, tBuG, MeAla, MeGly, MeIle, MeLeu, MeVal, MeNle, hCha, and Mso;

[0145] B1 is selected from any one of Val, Ile, Leu, Nle, Aha, MeIle, MeLeu, MeVal, and MeNle.

[0146] In certain embodiments, P1 is Asn, Glu, Arg, Lys, Cit, Orn, or Dab.

[0147] In certain embodiments, P1 is Cit, Orn, or Arg.

[0148] In a preferred embodiment, P1 is Arg.

[0149] In certain embodiments, P2 is Ala, Gly, Ile, Val, Leu, Pro, Nle, Dbu, Aha, or Dpr.

[0150] In certain embodiments, P2 is Aha, Aib, Nle, Ile, Val, or Leu.

[0151] In a preferred embodiment, P2 is Val.

[0152] In certain embodiments, P3 is Asn, Gin, Arg, Lys, or His.

[0153] In certain embodiments, P3 is Asn or Gin.

[0154] In a preferred embodiment, P3 is Gin.

[0155] In certain embodiments, P4 is Lys, Arg, His, Dab, Dbu, or Aha.

[0156] In certain embodiments, P4 is Lys, Dab, Dbu, or Aha.

[0157] In a preferred embodiment, P4 is Lys.

[0158] In certain embodiments, P5 is Phe, Tyr, Trp, His, Thi, or Phg.

[0159] In certain embodiments, P5 is Phe, Tyr, Trp, and His.

[0160] In a preferred embodiment, P5 is Tyr.

[0161] In certain embodiments, P6 is Ala, Gly, Val, Ile, Leu, Pro, Nle, Abu, Aha, or Aib.

[0162] In certain embodiments, P6 is Abu, Aib, Val, or Ile.

[0163] In a preferred embodiment, P6 is Ile.

[0164] In certain embodiments, B1 is Val, Ile, Leu, Nle, Aha, MeIle, MeLeu, MeVal, or MeNle.

[0165] In certain embodiments, B1 is Leu, Aha, or Nle.

[0166] In a preferred embodiment, B1 is Leu.

[0167] In certain embodiments, X1 is Ala, Gly, Ile, Leu, Pro, Phe, Val, Tyr, Trp, Aib, Nle, Pip, Pzp, Sar, tBuG, or a combination thereof.

[0168] In certain embodiments, X1 is 1-3 amino acid residues.

[0169] In a preferred embodiment, X1 is 2 amino acid residues.

[0170] In a preferred embodiment, X1is Pip-Phe, Pip-Tyr, Pip-Leu, Pip-Val, Pzp-Phe, Pzp-Tyr, Pzp-Leu, Pzp-Val, Sar-Ile, Sar-Leu, Sar-Val, tBuG-Ile, tBuG-Leu, tBuG-Val, Ala-Phe, Gly-Ile, Gly-Leu, Gly-Val, Ile-Val, Leu-Phe, Pro-Aib, Pro-Ala, Pro-Phe, Pro-Leu, Pro-Val, Pro-Trp, Pro-Tyr, or Val-Phe.

[0171] In another preferred embodiment, X1is Ala-Phe, Gly-Val, Leu-Phe, Ile-Val, Pro-Tyr, Val-Phe, Pro-Phe, or Pro-Ala.

[0172] In certain embodiments, X2is Aha, Dab, tBuG, Ala, Gly, Ile, Lys, Cys, Sar, Leu, Val, or a combination thereof.

[0173] In certain embodiments, X2is 2 to 5 amino acid residues.

[0174] In certain embodiments, X2is 4 amino acid residues.

[0175] In a preferred embodiment, X2is Aha-Ile-Gly-Ala, Dab-Ile-Gly-Ala, tBuG-Lys-Ala-Sar, Ala-Aha-Leu-Ile, Ala-Aha-Ala-Gly, Ala-Dab-Ala-Gly, Ala-Dab-Leu-Ile, Ala-Lys-Leu-Ile, Ala-Lys-Ala-Sar, Ala-Lys-Ala-Gly, Ala-Lys-Val-Leu, Gly-Aha-Ala-Gly, Gly-Dab-Ala-Gly, Gly-Lys-Ala-Gly, Gly-Lys-Val-Leu, Ile-Aha-Ala-Gly, Ile-Aha-Leu-Ile, Ile-Dab-Ala-Gly, Ile-Dab-Ala-Sar, Ile-Dab-Gly-Ala, Ile-Dab-Leu-Ile, Ile-Cys-Gly-Ala, Ile-Cys-Ala-Gly, Ile-Cys-Sar-Ala, Ile-Cys-Ala-tBuG, Ile-Cys-Leu-Ile, Ile-Lys-Leu-Ile, Ile-Lys-Sar-Ala, Ile-Lys-Ala-Gly, Ile-Lys-Ala-Sar, Ile-Lys-Gly-Ala, Lys-Ile-Gly-Ala, or Lys-Ile-tBuG-Ala.

[0176] In a preferred embodiment, X2is Ala-Lys-Leu-Ile, Ala-Lys-Ala-Gly, Ala-Lys-Val-Leu, Gly-Lys-Ala-Gly, Gly-Lys-Val-Leu, Ile-Lys-Gly-Ala, Ile-Cys-Gly-Ala, or Ile-Lys-Ala-Gly.

[0177] In certain embodiments, X3is Cit, Orn, Cys, Arg, or a combination thereof.

[0178] In certain embodiments, X3is 1-2 amino acid residues.

[0179] In certain embodiments, X3is 1 amino acid residue.

[0180] In a preferred embodiment, X3is Cit, Orn, Cys, or Arg.

[0181] In a preferred embodiment, X3is Arg.

[0182] In certain embodiments, X4 is Mso, Nle, Cys, Leu, Met, Phe, Tyr, Trp, or a combination thereof.

[0183] In certain embodiments, X4 is 1-3 amino acid residues.

[0184] In certain embodiments, X4 is 2 amino acid residues.

[0185] In a preferred embodiment, X4 is Mso-Phe, Mso-Tyr, Mso-Trp, Nle-Phe, Nle-Tyr, Nle-Trp, Cys-Phe, Cys-Tyr, Cys-Trp, Leu-Phe, Leu-Tyr, Leu-Trp, Met-Phe, Me-Tyr, or Met-Trp.

[0186] In a preferred embodiment, X4 is Met-Phe, Met-Tyr, or Met-Trp.

[0187] In certain embodiments, X5 is Pip, Pzp, Pro, or a combination thereof.

[0188] In certain embodiments, X5 is 1-2 amino acid residues.

[0189] In certain embodiments, X5 is 1 amino acid residue.

[0190] In certain embodiments, X5 is Pip, Pzp, or Pro.

[0191] In certain embodiments, X5 is Pro.

[0192] In certain embodiments, it comprises an amino acid sequence represented by Formula (I-1): R1-X 1-1 -X 1-2 -P1-X 2-1 -X 2-2 -X 2-3 -X 2-4 -P2-X3-P3-X 4-1 -X 4-2 -P4-X5-P5-P6-B1 Formula (I-1),

[0193] wherein R1, P1, P2, P3, P4, P5, P6, and B1 are as defined in any of the above;

[0194] X 1-1 , X 1-2 , X 2-1 , X 2-2 , X 2-3 , X 2-4 , X3, X4-1 , X 4-2 , X5is independently selected from natural amino acids, unnatural amino acids, chemical modifications of natural or unnatural amino acids.

[0195] In certain embodiments, X 1-1 is Pip, Pzp, Sar, tBuG, Ala, Gly, lie, Leu, Pro, or Val.

[0196] In a preferred embodiment, X 1-1 is Ala, Gly, lie, Leu, Pro, or Val.

[0197] In certain embodiments, X 1-2 is Aib, Nle, Ala, lie, Leu, Val, Tyr, Phe, or Trp.

[0198] In a preferred embodiment, X 1-2 is Ala, Phe, lie, Val, or Tyr.

[0199] In certain embodiments, X 2-1 is Aha, Dab, tBuG, Ala, Gly, lie, or Lys.

[0200] In a preferred embodiment, X 2-1 is Gly or lie.

[0201] In certain embodiments, X 2-2 is Cys, lie, Aha, Dab, or Lys.

[0202] In a preferred embodiment, X 2-2 is Cys or Lys.

[0203] In certain embodiments, X 2-3 is Sar, tBuG, Ala, Gly, Leu, or Val.

[0204] In a preferred embodiment, X 2-3 is Gly, Leu, or Val.

[0205] In certain embodiments, X 2-4 is Sar, tBuG, Ala, Gly, lie, or Leu.

[0206] In a preferred embodiment, X 2-4 is Ala, Gly, lie, or Leu.

[0207] In certain embodiments, X3is Cit, Orn, Cys, or Arg.

[0208] In a preferred embodiment, X3 is Cys or Arg.

[0209] In certain embodiments, X 4-1 is Mso, Nle, Cys, Leu or Met.

[0210] In a preferred embodiment, X 4-1 is Cys or Met.

[0211] In certain embodiments, X 4-2 is Phe, Tyr or Trp.

[0212] In a preferred embodiment, X 4-2 is Phe or Tyr.

[0213] In certain embodiments, X5 is Pip, Pzp or Pro.

[0214] In a preferred embodiment, X5 is Pro.

[0215] In certain embodiments, it comprises an amino acid sequence represented by formula (I-1-1):

[0216] R1-X 1-1 -X 1-2 -Arg-X 2-1 -X 2-2 -X 2-3 -X 2-4 -Val-X3-P3-X 4-1 -X 4-2 -Lys-X5-Tyr-P6-Leu formula (I-1-1),

[0217] wherein R1, X 1-1 , X 1-2 , X 2-1 , X 2-2 , X 2-3 , X 2-4 , X3, P3, X 4-1 , X 4-2 , P6, X5 are as defined in any of the preceding items.

[0218] In certain embodiments, the modification group of the N-terminal amino group is selected from Ac, Cbz, Boc, Fmoc, Alloc, Teoc, Pht, Tos, Tfa, Trt, Dmb, PMB, Bn, methoxycarbonyl and ethoxycarbonyl.

[0219] In certain embodiments, the modification group of the N-terminal amino group is Ac.

[0220] In certain embodiments, the amino acid sequence of the peptide compound is selected from any one of SEQ ID NO. 1 to SEQ ID NO. 108.

[0221] In a preferred embodiment, the peptide compound of formula (I) is a linear peptide.

[0222] The amino acid sequences of SEQ ID NO. 1 to SEQ ID NO. 108 are shown in Table 2.

[0223] Table 2

[0224] In a second aspect, the present application provides an isolated peptide compound or a derivative thereof or a pharmaceutically acceptable salt thereof, comprising:

[0225] (i) an amino acid sequence of formula (II):

[0226] R2-A1-P7-X6-P8-P9-X7-A2-X8-P 10 -B2 formula (II); or

[0227] (ii) an amino acid sequence having at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% sequence identity to the amino acid sequence of formula (II), and which retains the activity of the amino acid sequence of formula (II);

[0228] wherein,

[0229] R2 is a modification group of the N-terminal amino group or is absent;

[0230] X6, X7, X8 are independently selected from absent or are selected from natural amino acids, non-natural amino acids, chemical modifications of natural or non-natural amino acids, or a combination thereof;

[0231] A1 and A2 are each independently selected from any one of Cys, Sec and Pen;

[0232] P7 is selected from absent, Ser, Thr, Tyr, Trp, Cys, Thea, His, Sec, Pen, hSer, hCys, AlloT, sBzl, tBzl and yBzl;

[0233] P8 is selected from any one of Asn, Glu, Cys, Sec, Pro, Arg, Lys, His, Cit, Orn, Dab, Aha, Thea, Dimk, Isorn, 3AmiPhe, 4AmiPhe, 3GuPhe, 4GuPhe, hCys, hArg, AcLys, MeArg, MeLys, IPegDab, and SPegDab;

[0234] P9 is selected from any one of Phe, Tyr, Trp, His, 1-Nal, 2-Nal, 2AmPhe, 3AmPhe, 4AmPhe, 3AmiPhe, 4AmiPhe, 3GuPhe, 4GuPhe, 4-AmPyrr1, 4-AmPyrr2, 4-PhePyrr1, 4-PhePyrr2, 5-PhePyrr1, 5-PhePyrr2, 2Cl-Phe, 3Cl-Phe, 4Cl-Phe, 3,4Cl2-Phe, 3F-Phe, 4F-Phe, 4GuPhe, Bip, BnG, Bpa, C4al, C5al, Cha, Cpa, Phg, Tza, yBzl, hCha, hPhe, MePhe, Thi, Pro, Arg, and Leu;

[0235] P 10 is selected from any one of Ala, Gly, Val, Ile, Leu, Pro, Met, Nle, 4-AmPyrr1, 4-AmPyrr2, 4-PryAla, A2Bu, Abu, Aib, Cha, C4al, C5al, Dbu, Dpr, Pip, Pzp, Sar, tBuG, MeAla, MeGly, MeIle, MeLeu, MeVal, MeNle, hCha, and Mso;

[0236] B2 is selected from any one of Val, Ile, Leu, Trp, Nle, Aha, MeIle, MeLeu, MeVal, and MeNle.

[0237] In certain embodiments, A1 is Cys or Pen.

[0238] In a preferred embodiment, A1 is Cys.

[0239] In certain embodiments, A2 is Cys or Pen.

[0240] In a preferred embodiment, A2 is Cys.

[0241] In certain embodiments, P7 is Ser, Thr, Tyr, Trp, Cys, Thea, His, Sec, Pen, or absent.

[0242] In certain embodiments, P7 is Ser, Thr, Tyr, Trp, Thea, or His.

[0243] In a preferred and specific embodiment, P7 is Thr.

[0244] In certain embodiments, P8 is Asn, Glu, Cys, Pro, Arg, Lys, Cit, Orn, Dab, or Aha.

[0245] In a preferred embodiment, P8 is Arg, Cit, or Orn.

[0246] In a preferred and specific embodiment, P8 is Arg.

[0247] In certain embodiments, P9 is Phe, Tyr, Trp, His, Phg, Tza, Thi, Pro, Arg, or Leu.

[0248] In a preferred embodiment, P9 is Phe, Tyr, Trp, or His.

[0249] In a preferred and specific embodiment, P9 is Tyr.

[0250] In certain embodiments, P 10 is Ala, Gly, Val, lie, Leu, Pro, Nle, Abu, or Aib

[0251] In a preferred embodiment, P 10 is lie, Abu, or Aib.

[0252] In a preferred and specific embodiment, P 10 is lie.

[0253] In certain embodiments, B2 is Leu, Trp, Nle, or Aha.

[0254] In a preferred embodiment, B2 is Leu, Trp, or Nle.

[0255] In a preferred and specific embodiment, B2 is Leu.

[0256] In certain embodiments, X6 is Lys, Aha, Cit, Orn, Dab, Glu, Asn, Pro, Arg, Trp, Ser, Gly, lie, Ala, or a combination thereof.

[0257] In certain embodiments, X6 is 2 to 5 amino acid residues.

[0258] In certain embodiments, X6 is 3-5 amino acid residues.

[0259] In a preferred embodiment, X6 is Aha-Ser-Aha, Aha-Ser-Cit, Aha-Ser-Orn, Aha-Ser-Lys, Aha-Ser-Asn, Cit-Ser-Aha, Cit-Ser-Lys, Dab-Ser-Cit, Dab-Ser-Dab, Dab-Ser-Orn, Dab-Ser-Lys, Dab-Ser-Asn, Dab-Ser-Arg, Orn-Ser-Aha, Orn-Ser-Lys, Glu-Ser-Glu, Glu-Ser-Ile, Gly-Ser-Lys, Gly-Ser-Ile, Lys-Ser-Gly, Lys-Ser-Ile, Lys-Lys-Ile, Lys-Ser-Lys, Lys-Ser-Asn, Lys-Ser-Arg, Lys-Ser-Aha, Lys-Ser-Cit, Lys-Ser-Dab, Lys-Ser-Orn, Asn-Ser-Aha, Asn-Ser-Dab, Asn-Ser-Lys, Pro-Ser-Lys, Arg-Ser-Lys, Arg-Lys-Lys, Ser-Lys-Ile, Trp-Ser-Ile, Trp-Lys-Lys, Arg-Lys-Ala-Lys, or Arg-Lys-Pro-Lys-Pro.

[0260] In a preferred embodiment, X6 is Gly-Ser-Lys, Lys-Ser-Lys, Arg-Lys-Lys, Trp-Lys-Lys, Pro-Ser-Lys, Arg-Lys-Ala-Lys, or Arg-Lys-Pro-Lys-Pro.

[0261] In certain embodiments, X7 is absent, Abu, Aib, Dbu, Dpr, Sar, tBuG, Ala, Gly, Ile, Leu, Pro, Arg, or Val, or a combination thereof.

[0262] In certain embodiments, X7 is absent or 1-2 amino acid residues.

[0263] In certain embodiments, X7 is 1 amino acid residue.

[0264] In a preferred embodiment, X7 is Abu, Aib, Dbu, Dpr, Sar, tBuG, Ala, Gly, Ile, Leu, Pro, Arg, or Val.

[0265] In a specific and preferred embodiment, X7is lie.

[0266] In certain embodiments, X8is absent or is Tyr.

[0267] In a preferred embodiment, X8is absent.

[0268] In certain embodiments, it comprises an amino acid sequence represented by Formula (II-1): 6-1 -X 6-2 -X 6-3 -X 6-4 -X 6-5 -P8-P9-X7-A2-X8-P 10 -B2 Formula (II-1),

[0269] wherein R2, A1, P7, P8, P9, X7, A2, X8, P 10 , B2 are as defined in any of the above;

[0270] X 6-1 , X 6-2 , X 6-3 , X 6-4 , X 6-5 is independently selected from absent or from a natural amino acid, a non-natural amino acid, a chemical modification of a natural or non-natural amino acid.

[0271] In certain embodiments, X 6-1 is Aha, Cit, Dab, Orn, Glu, Gly, Lys, Asn, Pro, Arg, Ser, or Trp.

[0272] In certain embodiments, X 6-1 is Lys, Arg, or Trp.

[0273] In a preferred embodiment, X 6-1 is Lys or Arg.

[0274] In certain embodiments, X 6-2 is Ser or Lys.

[0275] In a specific and preferred embodiment, X 6-2 is Ser.

[0276] In certain embodiments, X 6-3 is absent, Pro, or Ala.

[0277] In a preferred embodiment, X 6-3 is Pro or Ala.

[0278] In certain embodiments, X 6-4 is Aha, Cit, Dab, Orn, Glu, Gly, lie, Lys, Asn, or Arg.

[0279] In a preferred embodiment, X 6-4 is lie or Lys.

[0280] In a specific and preferred embodiment, X 6-4 is Lys.

[0281] In certain embodiments, X 6-5 is absent or Pro.

[0282] In certain embodiments, it comprises an amino acid sequence represented by Formula (II-1-1): 6-1 -Ser-X 6-3 -X 6-4 -X 6-5 -P8-P9-X7-Cys-Ile-B2 Formula (II-1-1),

[0283] wherein R2, P7, X 6-1 , X 6-3 , X 6-4 , X 6-5 , P8, P9, X7, B2 are as defined in any of the above.

[0284] In certain embodiments, the peptide compound is a linear peptide or a cyclic peptide.

[0285] In certain embodiments, the modification group of the N-terminal amino group is selected from Ac, Cbz, Boc, Fmoc, Alloc, Teoc, Pht, Tos, Tfa, Trt, Dmb, PMB, Bn, methoxycarbonyl, and ethoxycarbonyl.

[0286] In certain embodiments, the modification group of the N-terminal amino group is Ac.

[0287] In a preferred embodiment, the peptide compound is a cyclic peptide.

[0288] In a preferred embodiment, the amino acid at position A1 and the amino acid at position A2 form a covalent bond to connect to form a cyclic peptide.

[0289] In a preferred embodiment, the amino acid at position A1 and the amino acid at position A2 form a disulfide bond to connect to form a cyclic peptide.

[0290] In the present application, when A1 and A2 are each independently selected from Cys or Pen, a disulfide bond can be formed with any cysteine in the polypeptide.

[0291] In the present application, when A1and A2are each independently selected from Sec, they form a cyclic peptide through a diselenide bond.

[0292] In certain embodiments, the amino acid sequence of the peptide compound is selected from any one of SEQ ID NO. 109 to SEQ ID NO. 234.

[0293] The amino acid sequences shown in SEQ ID NO. 109 to SEQ ID NO. 234 are shown in Table 3.

[0294] Table 3

[0295] In addition, although described as "a peptide consisting of a specific SEQ ID NO" in the present application, as long as the peptide has the same or corresponding activity as that of a peptide consisting of the amino acid sequence of the corresponding SEQ ID NO, it does not exclude mutations that can occur by the addition of meaningless sequences upstream or downstream of the amino acid sequence of the corresponding SEQ ID NO, or mutations that can occur naturally, or silent mutations thereof, and even when the sequence addition or mutation is present, it is obviously within the scope of the present application.

[0296] In a third aspect, the present application provides a drug conjugate having a structure represented by formula (III):

[0297] wherein a is an integer from 0 to 10;

[0298] E is a peptide compound or a derivative thereof or a pharmaceutically acceptable salt thereof according to any one of the above;

[0299] A is a cytotoxic agent;

[0300] L is a linker connecting E and A, and the wavy line in formula (III) indicates that L is covalently attached to a side chain residue or a terminal group of E.

[0301] In certain embodiments, a is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0302] In a fourth aspect, the present application also provides a pharmaceutical composition comprising a safe and effective amount of a peptide compound or a derivative thereof or a pharmaceutically acceptable salt thereof according to any one of the above or a drug conjugate or a pharmaceutically acceptable salt thereof according to the above, and a pharmaceutically acceptable carrier and / or excipient.

[0303] The formulation type of the composition according to the present application can be variously prepared in combination with the above-described pharmaceutically acceptable carriers. For example, for oral administration, the composition can be formulated into tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc. For injection, the composition can be formulated into a unit dose ampoule or a multiple dose container. The composition can also be formulated into solutions, suspensions, tablets, pills, capsules, sustained release formulations, etc.

[0304] In addition, the pharmaceutical composition of the present application can be prepared in any formulation type selected from tablets, pills, powders, granules, capsules, suspensions, liquid medicines for internal use, emulsions, syrups, sterile aqueous solutions, non-aqueous solvents, lyophilized formulations, and suppositories.

[0305] In addition, the composition can be formulated into a unit dosage form suitable for the patient's body, and preferably formulated into a formulation useful for a peptide drug according to typical methods in the pharmaceutical field, so as to be administered orally or parenterally, such as through the skin, intravenously, intramuscularly, intra-arterially, intramedullary, intrathecally, intraventricularly, pulmonary, transdermally, subcutaneously, intraperitoneally, intranasally, intragastrically, topically, sublingually, vaginally, or rectally, but is not limited thereto.

[0306] In addition, the peptide can be used in combination with various pharmaceutically acceptable carriers such as physiological saline or organic solvents. In order to increase stability or absorbability, a carbohydrate such as glucose, sucrose, or dextran, an antioxidant such as ascorbic acid or glutathione, a chelating agent, a low molecular weight protein, or other stabilizers can be used as a pharmaceutical preparation.

[0307] The administration dose and frequency of the pharmaceutical composition of the present application are determined in accordance with the type of active ingredient(s) together with various factors such as the disease to be treated, the administration route, the age, sex, and weight of the patient, and the severity of the disease.

[0308] The total effective dose of the composition of the present application can be administered to a patient in a single dose, or can be administered in multiple doses over a long period of time according to a fractionated treatment protocol. In the pharmaceutical composition of the present application, the content of the active ingredient(s) can vary depending on the severity of the disease. Specifically, the total daily dose of the peptide of the present application can be about 0.0001 mg to 500 mg per 1 kg of the body weight of the patient. However, the effective dose of the peptide is determined considering various factors including the age, body weight, health condition, sex, severity of disease, diet, and excretion rate of the patient in addition to the route of administration and frequency of treatment of the pharmaceutical composition. In this regard, one skilled in the art can easily determine the effective dose suitable for the specific use of the pharmaceutical composition of the present application. The pharmaceutical composition according to the present application is not particularly limited to the formulation and the route and method of administration, as long as it shows the effects of the present application.

[0309] Another aspect of the present application provides a method for treating a target disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide compound according to any one of the above or the pharmaceutical conjugate according to the above or a pharmaceutically acceptable salt thereof. The target disease can be a tumor and / or cancer.

[0310] As used herein, the term "subject" refers to a subject suspected of having a tumor and / or cancer, and a subject suspected of having a tumor and / or cancer refers to a mammal including a human, a rat, a domestic animal, etc., which has a tumor and / or cancer or is at risk of developing a tumor and / or cancer, but is not limited to any subject treatable with the above-described peptide of the present application or a composition containing the same.

[0311] The term "therapeutically effective amount" with respect to a pharmaceutical or pharmacologically active agent means a sufficient amount of the agent to achieve the intended effect without being toxic. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance, and the appropriate effective amount in each case can be determined by one skilled in the art according to routine experiments.

[0312] The therapeutic methods of the present application can comprise administering a pharmaceutically effective amount of a pharmaceutical composition comprising a peptide. The total daily dose of the compositions can be determined by a physician with the appropriate medical judgment, and the compositions can be administered once daily or in divided doses several times a day. For the purposes of this application, however, the therapeutically effective dose of the compositions for any particular patient will preferably vary according to factors such as the type and severity of the response desired, the specific compositions being used, including whether other agents are used in combination or alternation with it, the age, body weight, general health, sex, and diet of the patient, the time and route of administration, the rate of excretion, the duration of the treatment, other drugs used in combination or coincidentally with the specific compositions, and like factors as are well known in the medical arts.

[0313] In a fifth aspect, the present application provides the use of the peptide compound or derivative thereof or pharmaceutically acceptable salt thereof of any one of the first aspect and the second aspect, or the use of the drug conjugate or pharmaceutically acceptable salt thereof of the third aspect, or the use of the pharmaceutical composition of the fourth aspect, in the preparation of a medicament for preventing and treating a tumor / cancer.

[0314] In certain embodiments, the tumor / cancer overexpresses Sortilin.

[0315] In certain embodiments, the tumor / cancer comprises an adrenal cortex cancer, a bile duct cancer, a bladder cancer, a bone cancer, a brain cancer, a breast cancer, a cervical cancer, an endometrial cancer, a colorectal cancer, an esophageal cancer, a gastric cancer, a head and neck cancer, a kidney cancer, a leukemia, a liver cancer, a lung cancer, a lymphoma, a myeloma, a neuroblastoma, an ovarian cancer, a pancreatic cancer, a prostate cancer, a sarcoma, a rhabdoid tumor, a skin cancer, a testicular cancer, a thyroid cancer, a melanoma.

[0316] In certain embodiments, the cancer comprises an ovarian cancer, a breast cancer, a cervical cancer, an endometrial cancer, a pancreatic cancer, a colorectal cancer, a melanoma.

[0317] Other advantages and embodiments of the present application will be more readily understood and further appreciated as the description proceeds. The following will be illustrated by way of specific examples which will not be taken as limiting the scope of the application. Upon reading and understanding the content of this disclosure, one of ordinary skill in the art will readily perceive other advantages and purposes based on such an implementation and various modifications as can be made thereto without departing from the scope of the application.

[0318] Before further description of the application, it is to be understood that the application is not limited to the particular specific embodiments described herein; it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting as the scope of the present application.

[0319] Unless otherwise indicated, the experimental methods, detection methods, preparation methods disclosed in the present application all use conventional techniques in the field of molecular biology, biochemistry, chromatin structure and analysis, analytical chemistry, cell culture, recombinant DNA technology and related fields. These techniques are well described in the existing literature, see, for example, Sam brook et al. MOLECULAR CLONING: A LABORATORY MANUAL, Second edition, Cold Spring Harbor Laboratory Press, 1989 and Third edition, 2001; Ausubel et al. CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, 1987 and periodic updates; the series METHODS IN ENZYMOLOGY, Academic Press, San Diego; Wolffe, CHROMATIN STRUCTURE AND FUNCTION, Third edition, Academic Press, San Diego, 1998; METHODS IN ENZYMOLOGY, Vol. 304, Chromatin (P. M. Wassarman and A. P. Wolffe, eds.), Academic Press, San Diego, 1999; and METHODS IN MOLECULAR BIOLOGY, Vol. 119, Chromatin Protocols (P. B. Becker, ed.) Humana Press, Totowa, 1999, etc.

[0320] In addition to the specific methods, devices, materials used in the examples, according to the mastery of the prior art by those skilled in the art and the description of the present application, any method, device and material of the prior art similar or equivalent to the method, device and material described in the examples of the present application can also be used to implement the present application. Unless otherwise specified, the parts and percentages are parts by weight and weight percentages.

[0321] In the following examples,

[0322] The structure of the compound was determined by mass spectrometry (MS).

[0323] The determination of MS was carried out by (Agilent 6125B (ESI));

[0324] The HPLC determination uses an Agilent 1260 DAD high pressure liquid chromatograph (Gemini-NX-C18 4.6x250mm, 5μm);

[0325] Some common abbreviations used in the present application have the following meanings:

[0326] Fmoc refers to fluorenylmethyloxycarbonyl;

[0327] HBTU refers to 2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate;

[0328] DCM refers to dichloromethane;

[0329] DMF refers to N,N-dimethylformamide;

[0330] NMM refers to N-methylmorpholine;

[0331] TFA refers to trifluoroacetic acid;

[0332] EDT refers to 1,2-ethanedithiol.

[0333] Method for preparing linear polypeptides of Example 1

[0334] The synthesis of the peptide compounds of this example uses standard Fmoc chemistry, the specific method being as follows:

[0335] Each 1 mmol of the protected amino acid required for synthesis was weighed out and dissolved in DMF solution (63.4 mL) to prepare a 0.3 mmol / ml amino acid mixed solution for use.

[0336] The Fmoc-amino acid-Wang resin was poured into the reaction column, DCM was added and soaked for 30 minutes, then suctioned dry and an appropriate amount of deprotection solution (20% hexahydropyridine + 80% DMF) was added. After nitrogen stirring and agitation for 30 minutes, suction was performed. An appropriate amount of DMF was added, and after nitrogen agitation for 2 minutes, suction was performed, and the process was repeated 6 times.

[0337] An equal amount of protected amino acid Fmoc-Nle (norleucine)-OH and an appropriate amount of HBTU were added to the reaction column, and 6 times the molar amount of NMM was added to the resin. After nitrogen stirring and agitation for 30 minutes, suction was performed, and then DMF was added for washing. After nitrogen agitation for 2 minutes, suction was performed, and the process was repeated 3 times. 10-20 resin beads were taken into a small test tube, and buffer A (80% phenol, 20% anhydrous ethanol), buffer B (redistilled pyridine) and buffer C (5 grams of indanetrione, 100 mL of anhydrous ethanol) were each added two drops. Put into a dry heater and heat for 3 minutes (110°C), until the solution color is slightly yellow and the resin is colorless and transparent.

[0338] Repeat the above steps to connect the next amino acid, and so on until the last amino acid is connected, remove Fmoc and cap with acetic anhydride Ac, wash with DMF and methanol, and dry the resin, to obtain the resin polypeptide.

[0339] Put the dried resin polypeptide into a round-bottom flask, add cleavage solution (87.5% TFA, 5% benzyl mercaptan, 2.5% phenol, 2.5% EDT and 2.5% H2O), and constant temperature oscillation for 2 hours (25°C). Filter the resin particles, add 6-8 times the volume of anhydrous ether to the filtrate, stir while adding, and after the solid is precipitated, seal the tube, centrifuge for 3 minutes (4000 rpm), discard the supernatant, and add ether for washing, and centrifuge again, repeat 5 times.

[0340] Vacuum dry the washed polypeptide for 24 hours to obtain a white powder, which is the crude product of the desired polypeptide. Weigh the crude product and purify it by preparative liquid chromatography to obtain the linear polypeptide product of SEQ ID NO. 1.

[0341] Other polypeptide compounds prepared according to the above method, the amino acid sequence of the polypeptide compound is shown in Table 2.

[0342] Preparation method of cyclic peptide of the present application

[0343] The synthesis of the cyclic peptide compound of the present application uses standard Fmoc chemistry method, the specific method is as follows:

[0344] Weigh 1 mmol of each of the protected amino acids required for synthesis into a DMF solution (63.4 mL), and prepare a 0.3 mmol / ml amino acid mixed solution for use.

[0345] Pour the Fmoc-amino acid-Wang resin into the reaction column, soak for 30 minutes with DCM, dry, and then add an appropriate amount of deprotection solution (20% hexahydropyridine + 80% DMF), nitrogen stirring for 30 minutes, then dry. Add an appropriate amount of DMF, nitrogen stirring for 2 minutes, then dry, repeat 6 times.

[0346] Add an equal amount of protected amino acid Fmoc-Leu (leucine)-OH and an appropriate amount of HBTU to the reaction column, then add 6 times the molar amount of NMM to the resin, nitrogen stirring for 30 minutes, then dry, and then add DMF for washing, nitrogen stirring for 2 minutes, then dry, repeat 3 times. Take 10-20 resin in a small test tube, add buffer A (80% phenol, 20% anhydrous ethanol), buffer B (repeated pyridine) and buffer C (5 grams of indanone, 100 mL of anhydrous ethanol) each two drops. Put into the dry heater, heat for 3 minutes (110°C), until the solution color is yellowish, and the resin is colorless and transparent.

[0347] Repeat the above steps to link the next amino acid, and so on until the last amino acid is linked, remove Fmoc, and cap with acetic anhydride Ac. Wash with DMF and methanol, and dry the resin by suction. Finally, obtain the resin polypeptide.

[0348] Put the dried resin polypeptide into a round-bottom flask, add cleavage solution (87.5% TFA, 5% benzyl mercaptan, 2.5% phenol, 2.5% EDT and 2.5% H2O), and constant temperature oscillation for 2 hours (25°C). Filter the resin particles, add 6-8 times the volume of anhydrous ether to the filtrate, stir while adding, and centrifuge for 3 minutes (4000 rpm) after the solid is precipitated. Discard the supernatant and wash with ether, and repeat the centrifugation, which is repeated 5 times.

[0349] Vacuum dry the washed polypeptide for 24 hours to obtain a white powder, which is the crude product of the desired polypeptide.

[0350] Dissolve the above crude product in pure water, adjust the pH to 7.5-8.0, and stir for 24 hours. Adjust the pH to 7.0, and purify by preparative liquid chromatography to obtain the pure product of the cyclic peptide shown in SEQ ID NO. 109.

[0351] Other polypeptide compounds prepared according to the above method, and the amino acid sequences of the polypeptide compounds are shown in Table 3.

[0352] Example 3: Evaluation of the binding free energy of polypeptide and Sortilin protein

[0353] Download the crystal structure 3F6K.pdb of Sortilin-NT complex from the Protein Crystal Structure Database PDB, and delete the water molecules and other molecules except Sortilin and NT in the 3F6K crystal structure. Dock the polypeptide into the binding site of NT in Sortilin by ZDock (version 3.0.3) to obtain a Sortilin-polypeptide binding model (as shown in Figure 1). In the binding model, the Sortilin protein and the polypeptide are described using Amber force field parameters, and dissolved in a simulation box with periodic boundary conditions with Tip3p water molecules. The entire simulation system is subjected to 5000 steps of energy minimization using the steepest descent method, followed by 5000 steps of energy minimization using the conjugate gradient method, and then the backbone atoms of the protein and the polypeptide in the simulation system are fixed and subjected to 1 nanosecond of molecular dynamics simulation to fully optimize the simulation system. Finally, Gromacs is used to perform 20 nanoseconds of molecular dynamics simulation on the optimized simulation system at a temperature of 300K and in an NPT ensemble, and 100 binding conformations are selected from the last 5 nanoseconds of molecular dynamics simulation trajectory to calculate the binding free energy of the polypeptide and Sortilin using the MM / GB-SA method. The binding free energy of some polypeptides and Sortilin protein is shown in Table 4.

[0354] Table 4

[0355] In combination with the free energy calculation results shown in Table 4, the free energy of Sortilin binding to its natural substrate Neurotensin (NT) is -63.66 kcal / mol. The free energy of Sortilin binding to the polypeptide compounds shown in SEQ ID NO. 92-108, SEQ ID NO. 230-231 is all below -100 kcal / mol, which is much lower than the free energy of binding to NT. The polypeptide compounds shown in SEQ ID NO. 217-226 also have an advantage in free energy of binding to Sortilin compared to the natural substrate NT of Sortilin. The free energy of Sortilin binding to TH19P01 is -71.45 kcal / mol, which is much higher than the free energy of Sortilin binding to the polypeptide compounds shown in SEQ ID NO. 92-108, SEQ ID NO. 217-226, SEQ ID NO. 230-231. The above shows that the polypeptide compounds shown in SEQ ID NO. 92-108, SEQ ID NO. 217-226, SEQ ID NO. 230-231 have strong affinity for Sortilin.

[0356] Example 4: Polypeptide affinity evaluation for Sortilin

[0357] The affinity of the polypeptide for Sortilin was evaluated using the surface plasmon resonance (SPR) method and Biacore TM 8K SPR system. The biotinylated Sortilin protein with an Avi tag (Acrobiosystems, item number SON-H82E9-200ug) was captured and immobilized on a Neutravidin (Thermo Scientific, Cat. #31000)-coated CM5 sensor chip, and the capture protein was about 9 kRU. The experimental scheme for capturing Sortilin protein on a Biacore™ CM5 sensor chip is shown in Table 5.

[0358] Table 5

[0359] Rinse with 1x HBS-EP+ buffer (10 mM HEPES, 150 mM NaCl, 3 mM EDTA, 0.05% (v / v) surfactant P20 (Tween 20), pH 7.4). After dissolving the polypeptides in water, dilute with 1x HBS-EP+ buffer in a 2-fold gradient, resulting in 5 concentrations of samples, sequentially from low to high concentration, and perform SPR binding analysis at 25 °C with MCK module, see Table 6 for experimental protocol. The raw data of SPR were processed using Biacore TM 8K control software to depict resonance units (RU) into sensorgrams, and use the signal of blank sensorgram as blank correction. The association rate constant k a , dissociation rate constant k d and dissociation constant K D were calculated from the normalized SPR data under the steady state affinity model.

[0360] Table 6

[0361] The dissociation constants of some polypeptides to Sortilin are shown in Table 7, and the SPR affinity test results of NT and TH19P01, the natural substrates of Sortilin, are shown in Figures 2 and 3, with dissociation constants Kd of 258 nM and 2580 nM, respectively. Among them, the equilibrium dissociation constants K D of the polypeptide compounds represented by SEQ ID NO. 92, SEQ ID NO. 228 and SEQ ID NO. 231 are far lower than that of NT, the natural substrate of Sortilin; the equilibrium dissociation constants K D of the polypeptide compounds represented by SEQ ID NO. 223, SEQ ID NO. 229 and SEQ ID NO. 230 are slightly lower than that of NT, the natural substrate of Sortilin. This indicates that the affinities of these polypeptides to Sortilin are higher than that of NT, the natural substrate of Sortilin, among which the affinities of SEQ ID NO. 92 and SEQ ID NO. 231 are the most prominent, being 8.08 nM and 4.64 nM, respectively (the SPR affinity test results are shown in Figures 4 and 5, respectively). The equilibrium dissociation constants K D of the polypeptide compounds represented by SEQ ID NO. 92 and SEQ ID NO. 231 are about 1-3‰ of TH19P01, indicating that the affinities of the polypeptide compounds represented by SEQ ID NO. 92 and SEQ ID NO. 231 to Sortilin are much stronger than that of TH19P01.

[0362] Table 7

[0363] Example 5: Pharmacokinetic evaluation of polypeptides in mice

[0364] The polypeptides were dissolved in a solvent containing 5% DMSO, 45% PEG400 and 50% pure water, and prepared into a 0.4 mg / mL solution for use. After adaptive feeding, 7-9-week-old male ICR mice (Zhejiang Vantoll Life Experimental Animal Technology Co., Ltd.) were randomly divided into groups of 3, and intravenous injection (5 mL / kg) of the prepared polypeptide solution (dose of 2 mg / kg) was performed. Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours (a total of 8 time points) after intravenous administration, centrifuged and the plasma was collected. 10 μL of blood sample was added with 2 μL of methanol and 200 μL of methanol-acetonitrile solution (1:1, v / v) containing an internal standard, stirred and centrifuged for 15 minutes (4000 rpm), and the supernatant was detected for drug concentration by LC-MS / MS (AB Sciex Triple Quad 6500). The chromatographic column used was C18 2.6 μm 100A (50 mm*2.10 mm) Column; mobile phase A was 0.1% formic acid, 5 mM ammonium acetate aqueous solution; mobile phase B was 0.1% formic acid, acetonitrile solution; the column temperature was room temperature, the injection volume was 7 μL, and the gradient elution conditions are shown in Table 8; the mass spectrometry used an electrospray ionization source, and the ionization mode was positive ion selected reaction monitoring

[0365] Table 8

[0366] The pharmacokinetic test results are shown in Table 9, and the half-lives of SEQ ID NO. 223 and SEQ ID NO. 231 in plasma were significantly better than TH19P01. The half-life of the polypeptide compound represented by SEQ ID NO. 223 in plasma was as long as 27 minutes, and in particular, the half-life of the polypeptide compound represented by SEQ ID NO. 231 in plasma was as long as 45 minutes. According to reports, the half-life of Neurotensin in vivo is only 1.7 minutes (Holst Pedersen J, et al., J. Clin. Endocr. Metab. 1989, 68(2): 294-300). The above indicates that the stability of the polypeptide compounds represented by SEQ ID NO. 223 and SEQ ID NO. 231 in vivo is significantly better than TH19P01 and Neurotensin, the natural substrate of Sortilin.

[0367] Table 9

[0368] It should be understood that the above examples are exemplary and are not intended to limit the scope of the claims encompassing all possible embodiments. Various modifications and changes can be made thereto without departing from the scope of the application, which is set forth in the following claims. Likewise, the individual technical features of the above examples can be arbitrarily combined to form further embodiments of the application, which can not be explicitly described. Therefore, the above examples merely express several embodiments of the application, and do not limit the scope of the patent protection of the application.

Claims

1. An isolated peptide compound or a derivative thereof or a pharmaceutically acceptable salt thereof, characterized in that, It comprises: (i) an amino acid sequence comprising the amino acid sequence shown in Formula (I): R1-X1-P1-X2-P2-X3-P3-X4-P4-X5-P5-P6-B1 Formula (I); or (ii) an amino acid sequence having at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% sequence identity to the amino acid shown in Formula (I), and which retains the activity of the amino acid sequence shown in Formula (I); wherein, R1 is a modification group of the N-terminal amino group or is absent; X1, X2, X3, X4, X5 are independently selected from a natural amino acid, a non-natural amino acid, a chemical modification of a natural or non-natural amino acid, or a combination thereof; P1 is selected from any one of Asn, Glu, Cys, Sec, Arg, Lys, His, Cit, Orn, Dab, Aha, Thea, Dimk, Isorn, 3AmiPhe, 4AmiPhe, 3GuPhe, 4GuPhe, hCys, hArg, AcLys, MeArg, MeLys, IPegDab, and SPegDab; P2 is selected from any one of Ala, Gly, Ile, Val, Leu, Pro, Nle, Sar, tBuA, Dpr, A2Bu, Dbu, Abu, Aib, OctG, PipAla, PyrrAla, BnG, Cha, Cpa, C4al, C5al, Thea, MeAla, MeGly, MeIle, MeVal, MeLeu, MeNle, 4-AmPyrr1, 4-AmPyrr2, 4-PhePyrr1, 4-PhePyrr2, 5-PhePyrr1, 5-PhePyrr2, HyPro, Pip, Pzp, Ampc, Cpa, MeAla, MeGly, MeIle, MeVal, MeLeu, MeNle, hCha, and 4-PryAla; P3 is selected from any one of Asn, Gln, Trp, Arg, Lys, His, Cit, Orn, 2AmPhe, 3AmPhe, 4AmPhe, 3AmiPhe, 4AmiPhe, 3GuPhe, 4GuPhe, Cha, C4al, C5al, Thi, Tza, Mso, Aha, 4-AmPyrr1, 4-AmPyrr2, 4-PhePyrr1, 4-PhePyrr2, 5-PhePyrr1, 5-PhePyrr2, HyPro, Pip, Pzp, Ampc, Cpa, MeArg, hCha, hArg, and 4-PryAla; P4 is selected from any one of Asn, Gln, Trp, Arg, Lys, His, Cit, Orn, 2AmPhe, 3AmPhe, 4AmPhe, 3AmiPhe, 4AmiPhe, 3GuPhe, 4GuPhe, Cha, C4al, C5al, Thi, Tza, Mso, Aha, 4-AmPyrr1, 4-AmPyrr2, 4-PhePyrr1, 4-PhePyrr2, 5-PhePyrr1, 5-PhePyrr2, HyPro, Pip, Pzp, Ampc, Cpa, MeArg, hCha, hArg, and 4-PryAla; P4 is selected from any one of Lys, Arg, His, Gin, Pro, Dab, Cit, Orn, Thi, Tza, Aha, Aoc, HyPro, hArg, 3AmiPhe, 4AmiPhe, Dimk, AcLys, MeLys, MeArg, Pip, Pzp, IPegDab and SPegDab; P5 is selected from any one of Phe, Tyr, Trp, His, 1-Nal, Thi, 2-Nal, 2AmPhe, 3AmPhe, 4AmPhe, 3AmiPhe, 4AmiPhe, 3GuPhe, 4GuPhe, 4-AmPyrr1, 4-AmPyrr2, 4-PhePyrr1, 4-PhePyrr2, 5-PhePyrr1, 5-PhePyrr2, 2Cl-Phe, 3Cl-Phe, 4Cl-Phe, 3,4Cl2-Phe, 3F-Phe, 4F-Phe, 4GuPhe, Bip, BnG, Bpa, C4al, C5al, Cha, Cpa, Phg, Tza, yBzl, hCha, hPhe and MePhe; P6 is selected from any one of Ala, Gly, Val, Ile, Leu, Pro, Met, Nle, 4-AmPyrr1, 4-AmPyrr2, 4-PryAla, A2Bu, Abu, Aib, Cha, C4al, C5al, Dbu, Dpr, Pip, Pzp, Sar, tBuG, MeAla, MeGly, MeIle, MeLeu, MeVal, MeNle, hCha and Mso; B1 is selected from any one of Val, Ile, Leu, Nle, Aha, MeIle, MeLeu, MeVal and MeNle.

2. The peptide compound or a derivative thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein P1 is Asn, Glu, Arg, Lys, Cit, Orn or Dab, more preferably Cit, Orn or Arg, most preferably Arg; Preferably, P2 is Ala, Gly, Ile, Val, Leu, Pro, Nle, Dbu, Aha or Dpr, more preferably Aha, Aib, Nle, Ile, Val or Leu, most preferably Val; Preferably, P3 is Asn, Gin, Arg, Lys or His, more preferably Asn or Gin, most preferably Gin; Preferably, P4 is Lys, Arg, His, Dab, Dbu or Aha, more preferably Lys, Dab, Dbu or Aha, most preferably Lys; Preferably, P5 is Phe, Tyr, Trp, His, Thi or Phg, more preferably Phe, Tyr, Trp and His, preferably Tyr; Preferably, P6 is Ala, Gly, Val, lie, Leu, Pro, Nle, Abu, Aha or Aib, more preferably Abu, Aib, Val or lie, preferably lie; Preferably, B1 is Val, lie, Leu, Nle, Aha, MeIle, MeLeu, MeVal or MeNle, more preferably Leu, Aha or Nle, most preferably Leu; Preferably, X1 is Ala, Gly, lie, Leu, Pro, Phe, Val, Tyr, Trp, Aib, Nle, Pip, Pzp, Sar, tBuG or a combination thereof; Preferably, X2 is Aha, Dab, tBuG, Ala, Gly, lie, Lys, Cys, Sar, Leu, Val or a combination thereof; Preferably, X3 is Cit, Orn, Cys, Arg or a combination thereof; Preferably, X4 is Mso, Nle, Cys, Leu, Met, Phe, Tyr, Trp or a combination thereof; Preferably, X5 is Pip, Pzp, Pro or a combination thereof; Preferably, the modification group of the N-terminal amino group is selected from Ac, Cbz, Boc, Fmoc, Alloc, Teoc, Pht, Tos, Tfa, Trt, Dmb, PMB, Bn, methoxycarbonyl and ethoxycarbonyl.

3. The peptide compound or derivative thereof or pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that, X1 is 1 to 3 amino acid residues, preferably 2 amino acid residues, more preferably Pip-Phe, Pip-Tyr, Pip-Leu, Pip-Val, Pzp-Phe, Pzp-Tyr, Pzp-Leu, Pzp-Val, Sar-Ile, Sar-Leu, Sar-Val, tBuG-Ile, tBuG-Leu, tBuG-Val, Ala-Phe, Gly-Ile, Gly-Leu, Gly-Val, lie-Val, Leu-Phe, Pro-Aib, Pro-Ala, Pro-Phe, Pro-Leu, Pro-Val, Pro-Trp, Pro-Tyr or Val-Phe, most preferably Ala-Phe, Gly-Val, Leu-Phe, lie-Val, Pro-Tyr, Val-Phe, Pro-Phe or Pro-Ala; X1 is 1 to 3 amino acid residues, preferably 2 amino acid residues, more preferably Pip-Phe, Pip-Tyr, Pip-Leu, Pip-Val, Pzp-Phe, Pzp-Tyr, Pzp-Leu, Pzp-Val, Sar-Ile, Sar-Leu, Sar-Val, tBuG-Ile, tBuG-Leu, tBuG-Val, Ala-Phe, Gly-Ile, Gly-Leu, Gly-Val, lie-Val, Leu-Phe, Pro-Aib, Pro-Ala, Pro-Phe, Pro-Leu, Pro-Val, Pro-Trp, Pro-Tyr or Val-Phe, most preferably Ala-Phe, Gly-Val, Leu-Phe, lie-Val, Pro-Tyr, Val-Phe, Pro-Phe or Pro-Ala; Preferably, X2is 2 to 5 amino acid residues, preferably 4 amino acid residues, more preferably Aha-Ile-Gly-Ala, Dab-Ile-Gly-Ala, tBuG-Lys-Ala-Sar, Ala-Aha-Leu-Ile, Ala-Aha-Ala-Gly, Ala-Dab-Ala-Gly, Ala-Dab-Leu-Ile, Ala-Lys-Leu-Ile, Ala-Lys-Ala-Sar, Ala-Lys-Ala-Gly, Ala-Lys-Val-Leu, Gly-Aha-Ala-Gly, Gly-Dab-Ala-Gly, Gly-Lys-Ala-Gly, Gly-Lys-Val-Leu, Ile-Aha-Ala-Gly, Ile-Aha-Leu-Ile, Ile-Dab-Ala-Gly, Ile-Dab-Ala-Sar, Ile-Dab-Gly-Ala, Ile-Dab-Leu-Ile, Ile-Cys-Gly-Ala, Ile-Cys-Ala-Gly, Ile-Cys-Sar-Ala, Ile-Cys-Ala-tBuG, Ile-Cys-Leu-Ile, Ile-Lys-Leu-Ile, Ile-Lys-Sar-Ala, Ile-Lys-Ala-Gly, Ile-Lys-Ala-Sar, Ile-Lys-Gly-Ala, Lys-Ile-Gly-Ala or Lys-Ile-tBuG-Ala, most preferably Ala-Lys-Leu-Ile, Ala-Lys-Ala-Gly, Ala-Lys-Val-Leu, Gly-Lys-Ala-Gly, Gly-Lys-Val-Leu, Ile-Lys-Gly-Ala, Ile-Cys-Gly-Ala or Ile-Lys-Ala-Gly; Preferably, X3is 1 to 2 amino acid residues, preferably 1 amino acid residue, more preferably Cit, Orn, Cys or Arg, most preferably Arg; Preferably, X4is 1 to 3 amino acid residues, preferably 2 amino acid residues, more preferably Mso-Phe, Mso-Tyr, Mso-Trp, Nle-Phe, Nle-Tyr, Nle-Trp, Cys-Phe, Cys-Tyr, Cys-Trp, Leu-Phe, Leu-Tyr, Leu-Trp, Met-Phe, Me-Tyr or Met-Trp, most preferably Met-Phe, Met-Tyr or Met-Trp; Preferably, X5is 1 to 2 amino acid residues, preferably 1 amino acid residue, more preferably Pip, Pzp or Pro, most preferably Pro.

4. The peptide compound or derivative thereof or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein which comprises an amino acid sequence represented by formula (I-1): (I-1) R1-X 1-1 -X 1-2 -P1-X 2-1 -X 2-2 -X 2-3 -X 2-4 -P2-X3-P3-X 4-1 -X 4-2 -P4-X5-P5-P6-B1 Formula (I-1), wherein R1, P1, P2, P3, P4, P5, P6 and B1 are as defined in any one of claims 1 to 3; X 1-1 , X 1-2 , X 2-1 , X 2-2 , X 2-3 , X 2-4 , X3, X 4-1 , X 4-2 , X5 is independently selected from a natural amino acid, a non-natural amino acid, a chemical modification of a natural or non-natural amino acid.

5. The peptide compound or derivative thereof or pharmaceutically acceptable salt thereof according to claim 4, wherein, X 1-1 Pip, Pzp, Sar, tBuG, Ala, Gly, lie, Leu, Pro or Val, preferably Ala, Gly, lie, Leu, Pro or Val; Preferably, X is Aib, Nle, Ala, lie, Leu, Val, Tyr, Phe or Trp, preferably Ala, Phe, lie, Val or Tyr. 1-2 Preferably, X is Aib, Nle, Ala, lie, Leu, Val, Tyr, Phe or Trp, preferably Ala, Phe, lie, Val or Tyr. Preferably, X is Aha, Dab, tBuG, Ala, Gly, lie or Lys, preferably Gly or lie. 2-1 is Aha, Dab, tBuG, Ala, Gly, lie or Lys, preferably Gly or lie; Preferably, X is Cys, lie, Aha, Dab or Lys, preferably Cys or Lys. 2-2 is Cys, lie, Aha, Dab or Lys, preferably Cys or Lys; Preferably, X is S, tBuG, Ala, Gly, Leu or Val, preferably Gly, Leu or Val. 2-3 is S, tBuG, Ala, Gly, Leu or Val, preferably Gly, Leu or Val; Preferably, X is S, tBuG, Ala, Gly, lie or Leu, preferably Ala, Gly, lie or Leu. 2-4 is S, tBuG, Ala, Gly, lie or Leu, preferably Ala, Gly, lie or Leu; Preferably, X3 is Cit, Orn, Cys or Arg, preferably Cys or Arg. Preferably, X 4-1 is Mso, Nle, Cys, Leu or Met, preferably Cys or Met; Preferably, X 4-2 It can be Phe, Tyr, or Trp, preferably Phe or Tyr; Preferably, X5 is Pip, Pzp or Pro, preferably Pro.

6. The peptide compound or derivative thereof or pharmaceutically acceptable salt thereof according to claim 4 or 5, characterized in that, which comprises an amino acid sequence represented by formula (I-1-1): R1-X 1-1 -X 1-2 -Arg-X 2-1 -X 2-2 -X 2-3 -X 2-4 -Val-X3-P3-X 4-1 -X 4-2 -Lys-X5-Tyr-P6-Leu Formula (I-1-1), wherein R1, X 1-1 , X 1-2 , X 2-1 , X 2-2 , X 2-3 , X 2-4 , X3, P3, X 4-1 , X 4-2 , X5, P6 are as defined in any one of claims 4 or 5.

7. The peptide compound or derivative thereof or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein The amino acid sequence of the peptide compound is selected from any one of SEQ ID NO. 1 to SEQ ID NO.

108.

8. An isolated peptide compound of the formula: ###0002### or a derivative or a pharmaceutically acceptable salt thereof. which comprises: (i) an amino acid sequence represented by formula (II): R2-A1-P7-X6-P8-P9-X7-A2-X8-P 10 -B2 Formula (II); or (ii) an amino acid sequence having at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% sequence identity to the amino acid represented by formula (II), and which retains the activity of the amino acid sequence represented by formula (II); wherein, R2 is a modification group of the N-terminal amino group or is absent; X6, X7, X8 are independently selected from absent or from natural amino acids, unnatural amino acids, chemical modifications of natural or unnatural amino acids, or a combination thereof; A1 and A2 are each independently selected from any one of Cys, Sec and Pen; P7 is selected from absent, Ser, Thr, Tyr, Trp, Cys, Thea, His, Sec, Pen, hSer, hCys, AlloT, sBzl, tBzl and yBzl; P8 is selected from Asn, Glu, Cys, Sec, Pro, Arg, Lys, His, Cit, Orn, Dab, Aha, Thea, Dimk, Isorn, 3AmiPhe, 4AmiPhe, 3GuPhe, 4GuPhe, hCys, hArg, AcLys, MeArg, MeLys, IPegDab and SPegDab; P9 is selected from Phe, Tyr, Trp, His, 1-Nal, 2-Nal, 2AmPhe, 3AmPhe, 4AmPhe, 3AmiPhe, 4AmiPhe, 3GuPhe, 4GuPhe, 4-AmPyrr1, 4-AmPyrr2, 4-PhePyrr1, 4-PhePyrr2, 5-PhePyrr1, 5-PhePyrr2, 2Cl-Phe, 3Cl-Phe, 4Cl-Phe, 3,4Cl2-Phe, 3F-Phe, 4F-Phe, 4GuPhe, Bip, BnG, Bpa, C4al, C5al, Cha, Cpa, Phg, Tza, yBzl, hCha, hPhe, MePhe, Thi, Pro, Arg and Leu; P 10 selected from any one of Ala, Gly, Val, lie, Leu, Pro, Met, Nle, 4-AmPyrrl, 4-AmPyrr2, 4-PryAla, A2Bu, Abu, Aib, Cha, C4al, C5al, Dbu, Dpr, Pip, Pzp, Sar, tBuG, MeAla, MeGly, MeIle, MeLeu, MeVal, MeNle, hCha, and Mso; B2 is selected from any one of Val, lie, Leu, Trp, Nle, Aha, MeIle, MeLeu, MeVal and MeNle.

9. The peptide compound or derivative thereof or pharmaceutically acceptable salt thereof according to claim 8, wherein A1 and A2 are each independently Cys or Pen, preferably Cys; Preferably, P7 is Ser, Thr, Tyr, Trp, Cys, Thea, His, Sec, Pen or absent, more preferably Ser, Thr, Tyr, Trp, Thea or His, most preferably Thr; Preferably, P8 is Asn, Glu, Cys, Pro, Arg, Lys, Cit, Orn, Dab or Aha, more preferably Arg, Cit or Orn, most preferably Arg; Preferably, P9 is Phe, Tyr, Trp, His, Phg, Tza, Thi, Pro, Arg or Leu; more preferably Phe, Tyr, Trp or His, most preferably Tyr; Preferably, P 10 is Ala, Gly, Val, lie, Leu, Pro, Nle, Abu or Aib; more preferably lie, Abu or Aib, most preferably lie; Preferably, B2 is Leu, Trp, Nle or Aha; more preferably Leu, Trp or Nle, most preferably Leu; Preferably, X6 is Lys, Aha, Cit, Orn, Dab, Glu, Asn, Pro, Arg, Trp, Ser, Gly, lie, Ala or a combination thereof; Preferably, X7 is absent, Abu, Aib, Dbu, Dpr, Sar, tBuG, Ala, Gly, lie, Leu, Pro, Arg, Val or a combination thereof; Preferably, X8 is absent or is Tyr, more preferably absent; Preferably, the modification group of the N-terminal amino group is selected from Ac, Cbz, Boc, Fmoc, Alloc, Teoc, Pht, Tos, Tfa, Trt, Dmb, PMB, Bn, methoxycarbonyl and ethoxycarbonyl.

10. The peptide compound or derivative thereof or pharmaceutically acceptable salt thereof according to claim 8 or 9, characterized in that, X6 is 2-5 amino acid residues, preferably 3-5 amino acid residues, more preferably Aha-Ser-Aha, Aha-Ser-Cit, Aha-Ser-Orn, Aha-Ser-Lys, Aha-Ser-Asn, Cit-Ser-Aha, Cit-Ser-Lys, Dab-Ser-Cit, Dab-Ser-Dab, Dab-Ser-Orn, Dab-Ser-Lys, Dab-Ser-Asn, Dab-Ser-Arg, Orn-Ser-Aha, Orn-Ser-Lys, Glu-Ser-Glu, Glu-Ser-Ile, Gly-Ser-Lys, Gly-Ser-Ile, Lys-Ser-Gly, Lys-Ser-Ile, Lys-Lys-Ile, Lys-Ser-Lys, Lys-Ser-Asn, Lys-Ser-Arg, Lys-Ser-Aha, Lys-Ser-Cit, Lys-Ser-Dab, Lys-Ser-Orn, Asn-Ser-Aha, Asn-Ser-Dab, Asn-Ser-Lys, Pro-Ser-Lys, Arg-Ser-Lys, Arg-Lys-Lys, Ser-Lys-Ile, Trp-Ser-Ile, Trp-Lys-Lys, Arg-Lys-Ala-Lys or Arg-Lys-Pro-Lys-Pro, most preferably Gly-Ser-Lys, Lys-Ser-Lys, Arg-Lys-Lys, Trp-Lys-Lys, Pro-Ser-Lys, Arg-Lys-Ala-Lys or Arg-Lys-Pro-Lys-Pro; Preferably, X7 is absent or 1-2 amino acid residues, preferably 1 amino acid residue, more preferably Abu, Aib, Dbu, Dpr, Sar, tBuG, Ala, Gly, Ile, Leu, Pro, Arg or Val, most preferably Ile.

11. The peptide compound or derivative or pharmaceutically acceptable salt thereof according to any one of claims 8 to 10, wherein which comprises an amino acid sequence represented by formula (II-1): R2-A1-P7-X 6-1 -X 6-2 -X 6-3 -X 6-4 -X 6-5 -P8-P9-X7-A2-X8-P 10 -B2 Formula (II-1), wherein R2, A1, P7, P8, P9, X7, A2, X8, P 10 B2 is as defined in any one of claims 8 to 10; X 6-1 , X 6-2 , X 6-3 , X 6-4 , X 6-5 independent is selected from the absence or is selected from a natural amino acid, a non-natural amino acid, a chemical modification of a natural or non-natural amino acid.

12. The peptide compound or derivative thereof or pharmaceutically acceptable salt thereof according to claim 11, characterized in that, X 6-1 is Aha, Cit, Dab, Orn, Glu, Gly, Lys, Asn, Pro, Arg, Ser or Trp, more preferably Lys, Arg or Trp, most preferably Lys or Arg; Preferably, X is Ser or Lys, more preferably Ser. 6-2 is Ser or Lys, more preferably Ser; Preferably, X 6-3 is absent, Pro or Ala, more preferably Pro or Ala; Preferably, X is Aha, Cit, Dab, Orn, Glu, Gly, lie, Lys, Asn or Arg; more preferably, X is lie or Lys, most preferably, X is Lys. 6-4 Preferably, X is Aha, Cit, Dab, Orn, Glu, Gly, lie, Lys, Asn or Arg; more preferably, X is lie or Lys, most preferably, X is Lys. 6-4 Preferably, X is Preferably, X 6-5 is absent or Pro.

13. The peptide compound or derivative thereof or pharmaceutically acceptable salt thereof according to claim 11 or 12, characterized in that, which comprises an amino acid sequence represented by formula (II-1-1): R2-Cys-P7-X 6-1 -Ser-X 6-3 -X 6-4 -X 6-5 -P8-P9-X7-Cys-Ile-B2 Formula (II-1-1), wherein R2, P7, X 6-1 , X 6-3 , X 6-4 , X 6-5 , P8, P9, X7, B2 are as defined in any one of claims 11 or 12.

14. The peptide compound or derivative or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein The peptide compound of formula (I) is a linear peptide; Preferably, the peptide compound of formula (II) is a linear peptide or a cyclic peptide, preferably a cyclic peptide; Preferably, a covalent bond is formed between the amino acid at position A1 and the amino acid at position A2 to form a cyclic peptide, more preferably a disulfide bond or a diselenide bond is formed between the amino acid at position A1 and the amino acid at position A2 to form a cyclic peptide.

15. The peptide compound or derivative or pharmaceutically acceptable salt thereof according to any one of claims 8 to 14, wherein The amino acid sequence of the peptide compound is selected from any one of SEQ ID NO. 109 to SEQ ID NO.

234.

16. A drug conjugate or a pharmaceutically acceptable salt thereof, characterized in that, The drug conjugate has a structure shown in formula (III): wherein a is an integer from 0 to 10; Preferably, the peptide compound of formula (II) is a linear peptide or a cyclic peptide, preferably a cyclic peptide; E is a peptide compound of any one of claims 1 to 15, or a derivative or a pharmaceutically acceptable salt thereof; A is a cytotoxic agent; L is a linker connecting E and A, the wavy line in formula (III) indicates that L is covalently attached to a side chain residue or a terminal group of E.

17. A pharmaceutical composition comprising a peptide compound of any one of claims 1 to 15, or a derivative or a pharmaceutically acceptable salt thereof, or a drug conjugate of claim 16, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

18. Use of a peptide compound of any one of claims 1 to 15, or a derivative or a pharmaceutically acceptable salt thereof, or a drug conjugate of claim 16, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 17, in the manufacture of a medicament for the prevention and treatment of a tumor / cancer. Preferably, the tumor / cancer overexpresses Sortilin.

19. A method for treating a tumor and / or cancer, characterized in that, The method comprises administering to a subject in need thereof a therapeutically effective amount of a peptide compound of any one of claims 1 to 15, or a drug conjugate of claim 16, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 17.

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