EphA2-binding peptides to be examined and compositions comprising same

Abstract

The present technology relates generally to peptides that bind to Eph receptor A2 (EphA2), peptides that bind to the EphA2, and compositions comprising such peptides.

Description

Related Applications

[0001] This application claims the benefit of priority of U.S. Provisional Application No. 63 / 411,222, filed Sep. 29, 2022. The entire content of the foregoing application, including any drawings and sequence listings, is hereby expressly incorporated by reference herein. Joint Research Agreement

[0002] The subject matter disclosed herein was developed and the claimed invention was made by one or more parties to, or on behalf of one or more parties to, a Joint Research Agreement (JRA) within the meaning of 35 U.S.C. § 100(h) and 37 C.F.R. § 1.9(e) that was in effect on or before the effective filing date of the claimed invention. One or more parties to the JRA include PeptiDream, Inc. (Kanagawa, Japan) and RayzeBio, Inc. (San Diego, California, USA). The claimed invention is the result of activities carried out within the scope of the Joint Research Agreement. Technical Field

[0003] The present technology relates to peptides that bind to Eph receptor tyrosine kinase A2 (EphA2) and to compositions comprising such peptides. The invention also includes conjugates comprising the peptides (the peptides conjugated to one or more effectors and / or functional groups), conjugates of any substance such as a pharmaceutical composition (the pharmaceutical composition comprising the peptide ligand and the substance conjugate), and the use of the peptide ligand and the substance conjugate in the prevention, inhibition, or treatment of diseases or disorders characterized by EphA2 overexpression or reduced expression in diseased tissue (e.g., in tumors when EphA2 is overexpressed). Background Information

[0004] Eph receptor A2 (ephrin type-A receptor 2; EphA2) is a member of the receptor-type tyrosine kinase. Ephrin A (the ligand of EphA2) is a membrane protein, and thus cell-cell interaction is known to be necessary for signal transduction via EphA2. EphA2-related signals are known to play important roles in cell proliferation or differentiation. In addition, EphA2 is considered to be one of the important cancer-related proteins; EphA2 is overexpressed in some of human tumor cells, and reducing the EphA2 expression level using an anti-EphA2 antibody results in cancer cell proliferation (JP 2010246546). Therefore, an antibody that binds to EphA2 is expected to be a drug component against cancer. In addition, an antibody-drug conjugate including an anti-EphA2 antibody and an anticancer drug is expected to be a drug component against cancer, such as Medimmune (MedImmune LLC). However, such antibody-drug conjugates (ADCs) have not yet entered the pharmaceutical market.

[0005] In recent years, peptide-drug conjugates (PDCs) have been considered as a solution. Due to the properties of peptides (scientific papers inserted PD), peptides, especially cyclic peptides, will compensate for the weaknesses of ADCs and become an alternative drug component of ADCs.

[0006] Therefore, it has the potential to become a drug component against diseases associated with overexpression or reduced expression of EphA2. Additionally, a peptide that binds to EphA2 / has an affinity for EphA2 (EphA2-binding peptide) is used to target and transport an object having a pharmacological effect on EphA2, such as a low molecular weight compound, a medium molecular weight compound, a high molecular weight compound, a peptide, a protein, an antibody, and a nucleic acid.

[0007] Using the EphA2-binding peptide, the distribution and amount of EphA2 expression can be confirmed, for example, by measuring the binding of a fluorescently labeled or fluorescent-tagged peptide to EphA2. In addition, the affinity of a ligand for EphA2, or the affinity of a ligand for different types of EphA2, can be determined by using the EphA2-binding peptide.

[0008] Therefore, novel EphA2-binding peptides and compositions containing such EphA2-binding peptides are both useful and desirable. SUMMARY OF THE INVENTION

[0009] The invention described herein particularly provides a peptide (e.g., a cyclic peptide) that binds to EphA2 (especially human EphA2); its linker-attached peptide; its conjugate; its kit (e.g., a kit for use in a method for diagnosing a disease or disorder characterized by overexpression or reduced expression of EphA2 by determining the expression level of EphA2); a composition (e.g., a pharmaceutical composition) containing such an EphA2-binding peptide or its conjugate; and a method for using the same.

[0010] Specific, non-limiting, and illustrative aspects and embodiments of the invention described herein are provided below as numbered examples. As used herein, "(cyclic) peptide" refers to "peptide, such as cyclic peptide".

[0011] 1. A (cyclic) peptide having an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide comprises an amino acid sequence that includes one or several (e.g., 1-6) amino acid deletions, substitutions, and / or additions selected from the following: the amino acid sequence of SEQ ID NO:1 da-MeF-N-L-Hgl-MeF-W1Me-V-W1Me-T-E-C (SEQ ID NO:1) or a pharmaceutically acceptable salt thereof, wherein the (cyclic) peptide consists of 10 to 12 amino acid residues.

[0012] 2. The (cyclic) peptide according to Example 1, wherein 1-5 amino acids selected from the group consisting of the following are deleted: N at position 3, L at position 4, MeF at position 6, T at position 10, and E at position 11 of SEQ ID NO:1, optionally without additional additions and / or substitutions.

[0013] 3. The (cyclic) peptide according to Example 1 or 2, wherein one or several (e.g., 1, 2, 3, 4, or 5) amino acids are added.

[0014] 4. The (cyclic) peptide according to any one of Examples 1 to 3, wherein one or more amino acid residues selected from the following are substituted: MeF at position 2, MeF at position 6, V at position 8, and E at position 11.

[0015] 5. The (cyclic) peptide according to any one of Examples 1 to 4, wherein the peptide comprises an amino acid sequence that has 2 or fewer amino acids deleted from amino acid SEQ ID NO:1, optionally without additional additions and / or substitutions.

[0016] 6. The (cyclic) peptide according to Example 5, wherein 1-2 amino acids selected from the group consisting of the following are deleted: T at position 10 and E at position 11 of SEQ ID NO:1, optionally without additional additions and / or substitutions.

[0017] 7. A (cyclic) peptide having an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide comprises the amino acid sequence of formula (I) or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is an amino acid; X2 is an amino acid containing an aromatic ring, its N-methylated amino acid, or a variant thereof; X3 is a hydrophilic amino acid (e.g., N, Q, Cit, K, or a variant thereof), glycine (G), alanine (A), or a variant thereof (e.g., da, 2-aminoisobutyric acid (Aib)); X4 is a hydrophobic amino acid (e.g., leucine (L)), a hydrophilic amino acid (e.g., citrulline (Cit)), or a variant thereof; X5 is a hydrophilic amino acid or a variant thereof; X6 is a hydrophilic amino acid, an amino acid containing an aromatic ring, or its N-methylated amino acid; X7 is an amino acid containing an aromatic ring (e.g., W, F, or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, an N-methylated amino acid, or a variant thereof; X9 is an amino acid containing an aromatic ring (e.g., W or a variant thereof); X10 is absent or is a hydrophilic amino acid (e.g., threonine (T) or a variant thereof); X11 is absent or is a hydrophilic amino acid; and X12 is cysteine (C) or a variant thereof.

[0018] 8. The (cyclic) peptide according to Example 7, wherein X3 is a hydrophilic amino acid.

[0019] 9. The (cyclic) peptide according to Example 8, wherein X3 is an amino acid containing a charged side chain (e.g., K or a variant thereof), an amino acid containing a polar uncharged side chain (e.g., Q, Cit, N, or a variant thereof), or G, A, or a variant thereof.

[0020] 10. The (cyclic) peptide according to any one of Examples 7-9, wherein X4 is a hydrophobic amino acid.

[0021] 11. The (cyclic) peptide according to Example 10, wherein X4 is an amino acid containing a hydrophobic side chain (e.g., L), an amino acid containing a polar uncharged side chain (e.g., Cit or a variant thereof).

[0022] 12. The (cyclic) peptide according to any one of Examples 7-11, wherein X5 is a hydrophilic amino acid.

[0023] 13. The (cyclic) peptide according to Example 12, wherein X5 is an amino acid containing a charged side chain (e.g., E, Hgl, D, or a variant thereof) or an amino acid containing a polar uncharged side chain (e.g., Q, Cit, Hgn, N, or a variant thereof).

[0024] 14. A (cyclic) peptide as described in any one of Examples 7 - 13, wherein X6 is a hydrophilic amino acid.

[0025] 15. A (cyclic) peptide as described in Example 14, wherein X6 is an amino acid comprising a charged side chain (e.g., E, Hgl, D, or a variant thereof) or an amino acid comprising a polar uncharged side chain (e.g., Q, Cit, Hgn, N or a variant thereof).

[0026] 16. A (cyclic) peptide as described in any one of Examples 7 - 15, wherein X11 is a hydrophilic amino acid.

[0027] 17. A (cyclic) peptide as described in Example 16, wherein X11 is an amino acid comprising a charged side chain (e.g., E, Hgl, D, R, hArg, K or a variant thereof) or an amino acid comprising a polar uncharged side chain (e.g., Q, Cit, Hgn, N, or a variant thereof).

[0028] 18. A (cyclic) peptide as described in any one of Examples 1 - 17, wherein the peptide has the amino acid sequence of formula (I) or a pharmaceutically acceptable salt thereof, X1 - X2 - X3 - X4 - X5 - X6 - X7 - X8 - X9 - X10 - X11 - X12 Formula (I) X1 is an amino acid; X2 is F, or a variant thereof, wherein the unsubstituted phenyl ring of F is substituted with: (i) a phenyl ring substituted with 1 or 2 substituents each independently selected from: -OH, -CN, -C 1-3 alkyl (e.g., -CH3), or (ii) a 6 - membered heteroaryl ring optionally substituted with 1 or 2 substituents each independently selected from: -OH, -CN, -C 1-3 alkyl (e.g., -CH3), wherein the F or its structural variant is optionally N - methylated; X3 is a hydrophilic amino acid (e.g., N, Q, Cit, K or a variant thereof), G, Aib, Hgn, Ala, or a variant thereof (e.g., da); X4 is a hydrophobic amino acid (e.g., an amino acid having 4 or more carbon atoms in a side chain comprising a straight - chain, branched - chain or cyclic carbon chain), and wherein X4 is optionally N - methylated (e.g., Cit or a variant thereof); X5 is an amino acid (e.g., a hydrophilic amino acid; Dab, Dap, R, E or a variant thereof; or an amino acid with a functional side chain (e.g., non - glycine)); X6 is its N - methylated amino acid; X7 is an amino acid that is W, Y, or a variant thereof (e.g., an amino acid having a 6-membered aryl or heteroaryl, or a 9- or 10-membered bicyclic aryl or heteroaryl linked to the α-carbon through carbon (e.g., a methylene group), where the 6-, 9-, and 10-membered heteroaryls have one heteroatom (e.g., N), and where the 6-, 9-, and 10-membered aryl or heteroaryl is optionally substituted with 1 or 2 substituents independently selected from: –CH3, -ethyl, -Cl, and -F); X8 is an amino acid having –H on the α-amino group; X9 is W or Y or a variant thereof; (e.g., a variant of W); X10 is absent or a polar amino acid (e.g., T or a variant thereof); X11 is absent or an amino acid (e.g., a hydrophilic amino acid; Dab, Dap, R, E or a variant thereof; or an amino acid with a functional side chain (e.g., a non-glycine)); and X12 is C or a variant thereof.

[0029] 19. The (cyclic) peptide according to any one of embodiments 1 to 18, wherein the peptide has an amino acid sequence of formula (Ia) or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X12 Formula (Ia) wherein, X1 is an amino acid (e.g., a D-amino acid); X2 is an amino acid containing an aromatic ring, its N-methylated amino acid, or a variant thereof; X3 is a hydrophilic amino acid (e.g., N, Q, Cit, K or a variant thereof), G, A, or a variant thereof (e.g., da, Aib); X4 is a hydrophobic amino acid or a hydrophilic amino acid (e.g., Cit or a variant thereof); X5 is a hydrophilic amino acid (e.g., Dab, Dap, R, E, Q, D, K) or a variant thereof; X6 is a hydrophilic amino acid, an amino acid containing an aromatic ring (e.g., W, or F, or a variant thereof) or its N-methylated amino acid; X7 is an amino acid containing an aromatic ring (e.g., W, F, or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, or an N-methylated amino acid; X9 is an amino acid containing an aromatic ring (e.g., W, F or a variant thereof); and X12 is C or a variant thereof.

[0030] 20. The (cyclic) peptide according to any one of embodiments 1 to 18, wherein the peptide has an amino acid sequence according to formula (I) or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is an amino acid (e.g., D - amino acid); X2 is an amino acid containing an aromatic ring, its N - methylated amino acid, or a variant thereof; X3 is a hydrophilic amino acid (e.g., N, Q, Cit, K or a variant thereof), G, A, or a variant thereof (e.g., da, Aib); X4 is a hydrophobic amino acid or a hydrophilic amino acid (e.g., Cit or a variant thereof); X5 is a hydrophilic amino acid (e.g., Dab, Dap, R, E, Q, D, K) or a variant thereof; X6 is a hydrophilic amino acid, an amino acid containing an aromatic ring (e.g., W, or F, or a variant thereof) or its N - methylated amino acid; X7 is an amino acid containing an aromatic ring (e.g., W, F, or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, or an N - methylated amino acid; X9 is an amino acid containing an aromatic ring (e.g., W, F or a variant thereof); X10 is a hydrophilic amino acid (e.g., T, S, N, Q, K, Cit, or a variant thereof); X11 is a hydrophilic amino acid; and X12 is C or a variant thereof.

[0031] 21. The (cyclic) peptide according to any one of embodiments 1 to 20, wherein X1 is an amino acid (e.g., D - amino acid); X2 is F, Y, W, a variant thereof, or its N - methylated amino acid; X3 is N, Q, Cit, G, Aib, K, A, or a variant thereof; X4 is G, A, Cit, or a variant thereof (e.g., G substituted with a straight - chain or branched C 1-5 alkyl, G substituted with a C 3-7 cycloalkyl, or A substituted with a C 3-7 cycloalkyl); X5 is a hydrophilic L - amino acid, wherein the L - amino acid contains a functional group selected from: -NH2, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2 and -NHC(O)CH3; X6 is a hydrophilic amino acid, F, Y, W, their N-methylated amino acids, or variants thereof, wherein the hydrophilic amino acid comprises a functional group selected from: -C(O)OH, -C(O)NH2, and -NHC(O)CH3; X7 is F, W, or a variant thereof; X8 is G substituted with one or two straight-chain or branched C 1-5 alkyl, G substituted with C 3-7 cycloalkyl, A substituted with C 3-7 cycloalkyl, or a hydrophilic L-amino acid, wherein the hydrophilic L-amino acid comprises -NH2, one or more -OH, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3; or the hydrophilic amino acid comprises a zwitterion; X9 is F, W, or a variant thereof; X10 is absent, Q, S, K, Cit, N, T, or a variant thereof (e.g., Q, S, K, Cit, N, or T optionally substituted with straight-chain or branched C 1-5 alkyl) or an L-amino acid comprising -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3; X11 is absent, E, Q, R, Cit, K, D, or N, or a variant thereof; and X12 is C or a variant thereof.

[0032] 22. The (cyclic) peptide according to any one of embodiments 1 to 21, wherein the peptide has an amino acid sequence according to formula (I) or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is da, df3CON, dkCOpipzaa, dahp, dDab-NH2-Ph3-SO2F, dDap-NH2-Ph3-SO2F, dDap-NH2-Ph4-SO2F, dCit, Aib, G, norvaline, norleucine, d4PyCON, or dhAla; X2 is MeF, Me3Py, MeF3CON, MeF3F, Me4Py, or MeY(Me); X3 is absent, N, Q, Cit, G, Aib, Hgn, hCit, norCit, LysAc, OrnAc, Ala, or da; X4 is L, Cbg, Chg, Cba, Cha, Ahx, Dahp, Cit, I, V, norleucine or norvaline; X5 is Hgl, Hgn, Dab, Dap, DabAc, DapAc, R, hArg, E or D; X6 is absent, MeF, MeE, Me3Py, Me4Py, MeF4F, MeF4F, MeF4C or MeY; X7 is W1Me, W1Me7Cl, W1Me7N, W, F, 7-AzaTrp, W7Me, W1Et, W1Me7Br, W1Me7OMe or W1Me6O7Cl; X8 is V, KCOpipzaa, N, Cit, Q glucamine, hCit, K, KAc, Aib, Alb, DapAc, OrnAc, A, T, alT, norleucine, norvaline, Hgl, E, Hgn, Q, I or L; X9 is W1Me, W1Me7Cl, W1Me7N, F23dMe, W1Et, W7Me, W, F or 7-AzaTrp; X10 is absent, T, Q, S, Hgn, α-methylserine, hSer, hThr, N, OrnAc, LysAc, Cit or hCit; X11 is absent, E, Hgn, R, hArg, Cit, hCit, Hgl, Orn, D, N, Q, DapAc, OrnAc, DabAc, norCit; and X12 is C, hCys, CdMe, C3RMe, C3SMe, selenocysteine, dc or penicillamine.

[0033] 23. The (cyclic) peptide according to any one of Examples 18-22, wherein X7 is W1Me or a variant thereof; and X9 is W1Me or a variant thereof.

[0034] 24. The (cyclic) peptide according to any one of Examples 18-23, wherein X7 is W1Me, W1MeCl, W1MeBr, Nal1, Nal2, W1Et, 3Bzf, 3Bzt, F23dC, W1Me7N or F23dMe; X8 is V, KCOpipzaa, N, Cit, hCit, KAc, DapAc, OrnAc, A, T, alT, Aib, Alb, Q glucamine, Hgl, Q, E, Hgn or K; and X9 is W1Me, Nal1, W1Et, Nal21N, 3Bzf, 3Bzt, Nal18N, F23dMe or F23dC.

[0035] 25. The (cyclic) peptide according to any one of Examples 1 to 17, wherein the peptide comprises an amino acid sequence according to formula (I) or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is any amino acid, X2 is an amino acid having an aromatic ring or a variant thereof, X3 is N, X4 is a hydrophobic amino acid or a variant thereof; X5 is a hydrophilic amino acid or a variant thereof; X6 is a hydrophilic amino acid or an amino acid having an aromatic ring; X7 is W or a variant thereof; X8 is V or a hydrophilic amino acid or a variant thereof, X9 is W or a variant thereof; X10 is T or a variant thereof; X11 is a hydrophilic amino acid; X12 is C or a variant thereof (e.g., C).

[0036] 26. The (cyclic) peptide according to any one of Examples 1 to 17, wherein the peptide has an amino acid sequence according to formula (Ia) or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X12 Formula (Ia) wherein, X1 is any amino acid; X2 is an amino acid having an aromatic ring or a variant thereof; X3 is N or a variant thereof; X4 is a hydrophobic amino acid or a variant thereof, X5 is a hydrophilic amino acid or a variant thereof; X6 is a hydrophilic amino acid or an amino acid having an aromatic ring; X7 is W or a variant thereof; X8 is a hydrophilic amino acid or a variant thereof, X9 is W or a variant thereof; and X12 is C or a variant thereof.

[0037] 27. A (cyclic) peptide having an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide consists of: a sequence of formula (I), X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) or a pharmaceutically acceptable salt thereof, wherein each of X1, X2, X3, X4, X5, X6 and X8 is independently an amino acid; X7 is W1Me or a variant thereof; X9 is W1Me or a variant thereof; each of X10 and X11 is independently absent or is an amino acid; and X12 is cysteine (C) or a variant thereof; and, optionally, a linker that links the peptide to a payload molecule.

[0038] 28. The (cyclic) peptide according to any one of Examples 7-27, wherein the variant of the amino acid is selected from amino acids having one, two or three substituents based on the amino acid, and wherein the substituents are independently selected from halogen, -CN, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, oxo, -OH, -CO2H, -CO2-C1-C3 alkyl, -C(=O)NH2, -C(=O)NH(C1-C3 alkyl), -C(=O)N(C1-C3 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C3 alkyl), -S(=O)2N(C1-C3 alkyl)2, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C6-C 10 aryl, C3-C6 cycloalkyl, 6-10 membered heteroalkyl and 6-10 membered heteroaryl.

[0039] 29. The (cyclic) peptide according to Example 28, wherein the variant is selected from amino acids having one or two substituents based on the amino acid, and wherein the substituents are independently selected from halogen, -CN, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, oxo, -OH, -CO2H, -CO2-C1-C3 alkyl, -C(=O)NH2, -C(=O)NH(C1-C3 alkyl), -C(=O)N(C1-C3 alkyl)2 and C1-C6 alkyl.

[0040] 30. The (cyclic) peptide according to any one of Examples 7-29, wherein the variant is selected from amino acids having similar hydrophilicity or hydrophobicity compared to the reference amino acid.

[0041] 31. A (cyclic) peptide as described in any one of Examples 7 - 29, wherein the variant is selected from amino acids having the same functional groups as the reference amino acid, and wherein the variant has a different side chain length compared to the reference amino acid.

[0042] 32. A (cyclic) peptide as described in any one of Examples 7 - 31, wherein the variant has a molecular weight that varies by no more than 14, 28, 30, 45, or 60 g / mol compared to the reference amino acid.

[0043] 33. A (cyclic) peptide that has an affinity for ephrin type - A receptor 2 (EphA2), wherein the peptide has the amino acid sequence of formula (I), X1 - X2 - X3 - X4 - X5 - X6 - X7 - X8 - X9 - X10 - X11 - X12 Formula (I) wherein, X1 is any D - or L - amino acid; X2 has the structure, where ring A2 is phenyl or a 6 - membered heteroaryl (e.g., heteroaryl having 1 or 2 Ns); R X2 are each independently halogen, - CN, - NO2, - OH, - OR a , - OC(=O)R a , - OC(=O)OR b , - OC(=O)NR c R d , - SH, SF5, - SR a , - S(=O)R a , - S(=O)2R a , - S(=O)2NR c R d , - NR c R d , - NR b , - NR c R d , - NR b , - NR a , - NR b , - NR b , - NR b , - NR a , - C(=O)R a , - C(=O)OR b , - C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally and independently substituted by one or more R XA substituted; kx2 is 0, 1, 2 or 3; mx2 is 0, 1, 2, 3 or 4; R NX2 is H, C1-C6 alkyl or C1-C6 haloalkyl; *X1 represents the attachment point to X1; and, *X3 represents the attachment point to X3; X3 has the structure of, wherein kx3 is 0, 1, 2 or 3; NX3 is H, C1-C6 alkyl or C1-C6 haloalkyl; R X3 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; *X2 represents the attachment point to X2; and, *X4 represents the attachment point to X4; X4 is a hydrophobic amino acid (e.g., an amino acid having 4 or more carbon atoms in a side chain comprising a straight-chain, branched-chain or cyclic carbon chain), and wherein X4 is optionally N-alkylated by a C 1-3 alkyl group; X5 is a hydrophilic L-amino acid, such as an amino acid having the structure of, wherein: R NX5 is H, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl or heteroalkyl is optionally and independently substituted by one or more R XA substituted; R X5 is -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, SF5, -SR a , -S(=O)R a, -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b , -NR c R d , -NR b , -NR b )NR c R d , -NR b , -NR a , -NR b , -NR b , -NR b , -NR a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl or heteroalkyl is optionally and independently substituted by one or more R XA substituted; provided that R NX5 and R X5 at least one of which contains a moiety selected from: -OH, -NH2 and -NH- (e.g., -NH-C(=NH)-NH2, -CO-NH2, -NH2, -COOH, -C(OH)-C 0-6 alkyl, -NH-CO-C 1-6 alkyl); *X4 represents the point of attachment to X4; and, *X6 represents the point of attachment to X6; X6 is (e.g., N, F), wherein R NX6 is H, C1-C6 alkyl or C1-C6 haloalkyl; R X6 is -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, SF5, -SR a , -S(=O)R a , -S(=O)2Ra 、 -S(=O)2NR c R d 、 -NR c R d 、 -NR b C(=O)NR c R d 、 -NR b C(=NR b )NR c R d 、 -NR b C(=O)R a 、 -NR b C(=O)OR b 、 -NR b S(=O)2R a 、 -C(=O)R a 、 -C(=O)OR b 、 -C(=O)NR c R d 、 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally and independently substituted by one or more R XA substituted; *X5 represents the attachment point to X5; and, *X7 represents the attachment point to X7; X7 has the structure of, wherein R NX7 is H, C1-C6 alkyl or C1-C6 haloalkyl; Ring A7 is aryl or heteroaryl; R X7 are each independently halogen, -CN, -NO2, -OH, -OR a 、 -OC(=O)R a 、 -OC(=O)OR b 、 -OC(=O)NR c R d 、 -SH, SF5, -SR a 、 -S(=O)R a 、 -S(=O)2R a 、 -S(=O)2-halogen, -S(=O)2NR c R d 、 -NR c R d 、 -NR bC(=O)NR c R d 、 -NR b C(=O)R a 、 -NR b C(=O)OR b 、 -NR b S(=O)2R a 、 -C(=O)R a 、 -C(=O)OR b 、 -C(=O)NR c R d 、 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally and independently substituted by one or more R XA substituted; kx7 is 0, 1, 2 or 3; mx7 is 0, 1, 2, 3, 4 or 5; *X6 represents the attachment point to X6; and, *X8 represents the attachment point to X8; X8 is an L-amino acid with -H on the α-amino group; X9 has the structure of, where R NX9 is H, C1-C6 alkyl or C1-C6 haloalkyl; Ring A9 is aryl or heteroaryl; R X9 are each independently halogen, -CN, -NO2, -OH, -OR a 、 -OC(=O)R a 、 -OC(=O)OR b 、 -OC(=O)NR c R d 、 -SH, SF5, -SR a 、 -S(=O)R a 、 -S(=O)2R a 、 -S(=O)2NR c R d 、 -NR c R d 、 -NR b C(=O)NR c R d 、 -NR b C(=O)R a 、 -NRb C(=O)OR b 、 -NR b S(=O)2R a 、 -C(=O)R a 、 -C(=O)OR b 、 -C(=O)NR c R d 、 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally and independently substituted by one or more R XA substituted; kx9 is 0, 1, 2 or 3; mx9 is 0, 1, 2, 3, 4 or 5; *X8 represents the attachment point to X8; and, *XC represents the attachment point to (i) X10 or (i) X12 when both X10 and X11 are absent; X10 is absent or is an L-amino acid; X11 is absent or is an L-amino acid; provided that when X10 is absent, then X11 is also absent; and X12 is an L-amino acid having a reactive thiol group, such as Cys and Cys variants; each R a independently is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl) or C1-C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more R; each R b independently is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more R; each R c and Rd independently is hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 aminoalkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a C1-C6 alkyl(cycloalkyl) group, a C1-C6 alkyl(heterocycloalkyl) group, a C1-C6 alkyl(aryl) group or a C1-C6 alkyl(heteroaryl) group; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl group is independently optionally substituted by one or more R; or R c and R d together with the atom to which they are attached form a heterocycloalkyl group optionally substituted by one or more R; and each R and R XA independently is halogen, -CN, -OH, -OC1-C6 alkyl, SF5, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NR b C(=NR b )NR c R d 、-NHC(=O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; Optionally, the peptide is linked to a payload molecule via a linker.

[0044] 34. The (cyclic) peptide according to embodiment 33, wherein ring A7 is a 6-membered aryl or heteroaryl group, or a 9- or 10-membered bicyclic aryl or heteroaryl group, and the 6-, 9- or 10-membered heteroaryl group has one heteroatom selected from N, O and S.

[0045] 35. The (cyclic) peptide according to embodiment 33 or 34, wherein R NX7 is H.

[0046] 36. The (cyclic) peptide according to any one of embodiments 33 to 35, wherein each R X7 is independently selected from -CH3, -ethyl, -Cl and -F, and mx7 is 0, 1 or 2.

[0047] 37. The (cyclic) peptide according to embodiment 33, wherein X7 is W1Me, Nal1, Nal2, W1Et, Nal21N, 3Bzf, 3Bzt, Nal15N, Nal14N, Nal24N, Nal28N, F23dMe, F23dC, W1Me7N or W1Me7Cl.

[0048] 38. The (cyclic) peptide according to embodiment 37, wherein X7 is W1Me, F23dMe or W1Me7Cl.

[0049] 39. The (cyclic) peptide according to any one of embodiments 33 to 38, wherein X9 is each R X9 independently selected from -OH, CN, NH2, C1-C3 alkyl, -Cl, -F, -Br, -CONH2 and -SO2F.

[0050] 40. The (cyclic) peptide according to any one of embodiments 33 to 39, wherein

[0051] 41. The (cyclic) peptide according to any one of embodiments 33 to 40, wherein R X9 are each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl.

[0052] 42. The (cyclic) peptide according to any one of embodiments 33 to 38, wherein X9 is W1Me, W, Nal1, W1Et, Nal21N, 3Bzf, 3Bzt, Nal14N, Nal18N, F23dMe, F23dC, or W1Et.

[0053] 43. The (cyclic) peptide according to embodiment 42, wherein X9 is W1Me or F23dMe.

[0054] 44. The (cyclic) peptide according to any one of Examples 33 to 43, wherein ring A2 is a 6-membered heteroaryl containing 1 or 2 Ns.

[0055] 45. The (cyclic) peptide according to any one of Examples 33 to 44, wherein R X5 is C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -C 0-6 alkylene-NH-C(=NH)-NH2, -C 0-6 alkylene-CO-NH2, -C 0-6 alkylene-COOH or -NH-CO-C 1-6 alkyl.

[0056] 46. The (cyclic) peptide according to any one of Examples 27-33, wherein X7 is W1Me, W1MeCl, W1MeBr, Nal1, Nal2, W1Et, 3Bzf, 3Bzt, F23dC, W1Me7N or F23dMe; X8 is V, KCOpipzaa, Hse, N, Cit, hCit, KAc, DapAc, OrnAc, T, alT, Aib, Alb, Q-reduced glucosamine, Hgl, E, Hgn, MeF, 3Py6NH2, W1Me, A, Q or K; and X9 is W1Me, Nal1, W1Et, Nal21N, 3Bzf, 3Bzt, Nal18N, F23dMe or F23dC.

[0057] 47. The (cyclic) peptide according to Example 24 or 46, wherein X7 is W1Me; X8 is V; and, X9 is W1Me.

[0058] 48. The (cyclic) peptide according to any one of Examples 1-47, wherein the peptide or its pharmaceutically acceptable salt has a cyclic structure in which the first amino acid (or X1) is covalently linked to the last amino acid (or X12).

[0059] 49. The (cyclic) peptide according to any one of Examples 1-48, wherein the peptide or its pharmaceutically acceptable salt has a cyclic structure having an amino acid and a cysteine residue or a variant thereof at the first residue X1, and wherein the amino acid at X1 forms a covalent bond with the cysteine residue or a variant thereof.

[0060] 50. The (cyclic) peptide according to any one of Examples 1-49, wherein the peptide has a monocyclic structure.

[0061] 51. The (cyclic) peptide as described in Example 50, wherein the amino acid X1 forms a covalent bond with cysteine or a variant thereof.

[0062] 52. The (cyclic) peptide as described in any one of Examples 1 - 51, wherein the peptide has the structure of formula (I - 1), wherein R 1 is selected from the group consisting of: NH2 and OH; R 2 is selected from the group consisting of: H or C 1-3 alkyl; R 3 is selected from the group consisting of: H or C 1-3 alkyl; wherein X1 to X11 have the definitions as described in formula (I).

[0063] 53. The (cyclic) peptide as described in Example 52 or a pharmaceutically acceptable salt thereof, wherein the peptide having the structure of formula (I - 1) has the structure of formula (I - 2),

[0064] 54. The (cyclic) peptide as described in any one of Examples 1 - 53, wherein the peptide or its salt comprises an amino acid sequence that is at least 95% identical to a sequence selected from SEQ ID NO: 1 - 171, or a sequence having up to 1, 2, 3, 4, or 5 substitutions by conservative variants compared to any one of the sequences selected from SEQ ID NO: 1 - 171.

[0065] 55. The (cyclic) peptide as described in any one of Examples 1 - 54, wherein the peptide or its salt (a) consists of an amino acid sequence selected from SEQ ID NO: 1 - 171; or (b) is not SEQ ID NO: 1.

[0066] 56. The (cyclic) peptide as described in Example 55, wherein the peptide consists of an amino acid sequence selected from SEQ ID NO: 1 - 122, 159 - 163, and 165 - 171, and the peptide has a cyclic structure that has a cysteine residue or a variant thereof at the 12th residue, and wherein the amino acid at X1 (e.g., a chloroacetylated amino acid) forms a covalent bond with the cysteine residue or a variant thereof at the 12th residue (e.g., by reacting the chloroacetyl group in the X1 amino acid with the cysteine residue or a variant thereof).

[0067] 57. The (cyclic) peptide as described in Example 55, wherein the peptide consists of an amino acid sequence selected from SEQ ID NOs: 123 - 149 and 164, and the peptide has a cyclic structure which has a cysteine residue or a variant thereof at the 10th residue, and wherein the amino acid at X1 (e.g., chloroacetylated amino acid) forms a covalent bond with the cysteine residue or a variant thereof at the 10th residue.

[0068] 58. The (cyclic) peptide as described in any one of Examples 1 - 57, wherein as determined by K in surface plasmon resonance (SPR) analysis d the peptide has a binding affinity for human EphA2 of at most 100 nM.

[0069] 59. The (cyclic) peptide as described in Example 58, wherein as determined by K in surface plasmon resonance (SPR) analysis d the peptide has a binding affinity for human EphA2 of at most 1 nM.

[0070] 60. The (cyclic) peptide as described in any one of Examples 1 - 59, wherein the peptide binds to the ligand - binding domain (LBD) of EphA2.

[0071] 61. The (cyclic) peptide as described in any one of Examples 1 - 60, wherein the peptide interacts with human EphA2 at one or more of the following amino acid residues: Asp53, Met55, Asn57, Met59, Met66, Thr101, Arg103, Phe156, Glu157, Arg159, Val161, Val189, and Ala190.

[0072] 62. The (cyclic) peptide as described in any one of Examples 1 - 61, wherein the peptide interacts with human EphA2 at Asp53 and Glu157.

[0073] 63. The (cyclic) peptide as described in any one of Examples 1 - 62, wherein the peptide has a plasma half - life (T 1 / 2 ) of at least 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 minutes as determined in vitro in human plasma at 37°C.

[0074] 64. The (cyclic) peptide as described in Example 63, wherein the peptide has a plasma half - life (T 1 / 2 ) of at least 250 minutes as determined in vitro in human plasma at 37°C.

[0075] 65. The (cyclic) peptide as described in any one of Examples 1 - 64, which is covalently linked to a linker that connects the peptide to a payload molecule.

[0076] 66. The (cyclic) peptide as described in embodiment 65, wherein the linker is attached to the peptide via a non-terminal amino acid residue of the peptide.

[0077] 67. The (cyclic) peptide as described in embodiment 66, wherein the linker is attached to the 5th amino acid residue or X5.

[0078] 68. The (cyclic) peptide as described in embodiment 66, wherein the linker is attached to the 8th amino acid residue or X8.

[0079] 69. The (cyclic) peptide as described in embodiment 66, wherein the linker is attached to the 11th amino acid residue or X11.

[0080] 70. The (cyclic) peptide as described in any one of embodiments 65 to 69, wherein the linker is attached to a lysine of the peptide.

[0081] 71. The (cyclic) peptide as described in any one of embodiments 65 to 70, wherein the linker is attached to the peptide via the N-terminus of the peptide.

[0082] 72. The (cyclic) peptide as described in any one of embodiments 65 to 70, wherein the linker is attached to the peptide via the C-terminus of the peptide.

[0083] 73. The (cyclic) peptide as described in any one of embodiments 65 to 72, wherein the linker is a bond.

[0084] 74. The (cyclic) peptide as described in any one of embodiments 65 to 72, wherein the linker contains 3 to 30 spacer atoms between the payload molecule and the peptide.

[0085] 75. The (cyclic) peptide as described in any one of embodiments 65 to 72, wherein the linker contains 6 to 18 spacer atoms between the payload molecule and the peptide.

[0086] 76. The (cyclic) peptide as described in embodiment 74 or 75, wherein the spacer atoms contain 1 to 6 nitrogens and 0 to 4 oxygens.

[0087] 77. The (cyclic) peptide as described in any one of embodiments 65 - 72 and 74 - 76, wherein the linker contains one or more amino acid residues.

[0088] 78. The (cyclic) peptide as described in embodiment 77, wherein the linker contains one or more amino acids selected from lysine residues, alanine residues, or phenylalanine residues.

[0089] 79. The (cyclic) peptide as described in any one of embodiments 65 - 72 and 74 - 78, wherein the linker contains one or more structures selected from the following: AEEA, AEEP, AEEEP, and AEEEEP.

[0090] 80. A (cyclic) peptide as described in any one of Examples 65 - 72, wherein the linker has the structure of formula (II - 1) wherein each L is independently -O-, –NR L -, –N(R L )2-, -OP(=O)(OR L )O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR L -, -NR L C(=O)-, -OC(=O)NR L -, -NR L C(=O)O-, -NR L C(=O)NR L -, -NR L C(=S)NR L -, -CR L =N-, -N=CR L , -NR L S(=O)2-, -S(=O)2NR L -, -C(=O)NR L S(=O)2-, -S(=O)2NR L C(=O)-, substituted or unsubstituted C3 - C 15 cycloalkyl, substituted or unsubstituted C1 - C 12 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1 - C 30 alkylene, substituted or unsubstituted C2 - C 30 alkenylene, substituted or unsubstituted C2 - C 30 alkynylene, substituted or unsubstituted C1 - C 30 heteroalkylene, -(C1 - C 30 alkylene)-O-, -O-(C1 - C 30 alkylene)-, -(C1 - C 30 alkylene)-NR L -, -NR L -(C1 - C 30 alkylene)-, -(C1 - C 30 alkylene)-N(R L )2- or -N(R L )2-(C1 - C 30 alkylene)-; and each RL independently is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and n is from 1 to 20.

[0091] 81. The (cyclic) peptide according to Example 80, wherein the linker comprises a structure of formula (II-1a), wherein L 1 and L 3 each independently is -O-, –NR L -, –N(R L )2-, -OP(=O)(OR L )O-, -S-, -S(=O)-, -S(=O)2-, -CH=CH-, =CH-, -C≡C-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR L -, -NR L C(=O)-, -OC(=O)NR L -, -NR L C(=O)O-, -NR L C(=O)NR L -, -NR L S(=O)2-, -S(=O)2NR L -, -C(=O)NR L S(=O)2- or -S(=O)2NR L C(=O)-; and L 2 is absent, substituted or unsubstituted C1-C 30 alkylene, or substituted or unsubstituted C1-C 30 heteroalkylene.

[0092] 82. The (cyclic) peptide according to Example 81, wherein L 1 is -NH-.

[0093] 83. The (cyclic) peptide according to Example 81 or 82, wherein L 2 is substituted or unsubstituted C1-C 30 alkylene, or substituted or unsubstituted C1-C 30 heteroalkylene.

[0094] 84. The (cyclic) peptide as described in Example 81 or 82, wherein L 2 is a substituted or unsubstituted C1-C 18 alkylene, or a substituted or unsubstituted C1-C 18 heteroalkylene.

[0095] 85. The (cyclic) peptide as described in any one of Examples 81 to 84, wherein L 2 is optionally substituted with one or more substituents selected from the following: -OH, -SH, oxo, amino, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, -C(=O)OR L , -OC(=O)R L , -OC(=O)OR L , -C(=O)N(R L )2, -NR L C(=O)R L , -OC(=O)N(R L )2 and -NR L C(=O)OR L ; and the C1-C6 alkyl is further optionally substituted with one or more substituents selected from the following: -OH, -SH, oxo, amino, C6-C 10 aryl, 6- to 10-membered heteroaryl, -C(=O)OR L , -OC(=O)R L , -OC(=O)OR L , -C(=O)N(R L )2, -NR L C(=O)R L , -OC(=O)N(R L )2 and -NR L C(=O)OR L .

[0096] 86. The (cyclic) peptide as described in any one of Examples 81-85, wherein L 3 is -NH-.

[0097] 87. The (cyclic) peptide as described in Example 81, wherein the linker has the following structure:

[0098] 88. The (cyclic) peptide as described in Example 81, wherein the linker has the following structure

[0099] 89. The (cyclic) peptide according to any one of Examples 1 - 88, wherein the peptide is a peptide having the formula (I), and wherein when the peptide binds to human EphA2, amino acid residue X7 is located less than from Phe156 of human EphA2.

[0100] 90. The (cyclic) peptide according to Example 89, wherein amino acid residue X7 is located less than from Phe156.

[0101] 91. The (cyclic) peptide according to Example 89, wherein amino acid residue X7 is located less than from Phe156.

[0102] 92. The (cyclic) peptide according to any one of Examples 1 - 91, wherein the peptide is a peptide having the formula (I), and wherein when the peptide binds to human EphA2, amino acid residue X9 is located less than from Phe156 of human EphA2.

[0103] 93. The (cyclic) peptide according to Example 92, wherein amino acid residue X9 is located less than from Phe156.

[0104] 94. The (cyclic) peptide according to Example 93, wherein amino acid residue X9 is located less than from Phe156.

[0105] 95. The (cyclic) peptide according to any one of Examples 1 - 94, wherein the peptide is a peptide having the formula (I), and wherein when the peptide binds to human EphA2, amino acid residue X8 is located less than from Phe156 of human EphA2.

[0106] 96. The (cyclic) peptide according to any one of Examples 89 - 95, wherein the human EphA2 comprises the sequence of SEQ ID NO: 276 or SEQ ID NO: 277.

[0107] 97. A (cyclic) peptide that has an affinity for ephrin type - A receptor 2 (EphA2) and competes with a peptide having an amino acid sequence with one or several amino acid deletions, substitutions, or additions including the following for binding to human EphA2: the amino acids of SEQ ID NO: 1 da - MeF - N - L - Hgl - MeF - W1Me - V - W1Me - T - E - C (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof.

[0108] 98. A (cyclic) peptide that has an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide competes with a peptide having the structure of formula (I) or a pharmaceutically acceptable salt thereof for binding to human EphA2, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is an amino acid; X2 is an amino acid containing an aromatic ring, its N-methylated amino acid, or a variant thereof; X3 is a hydrophilic amino acid (e.g., N, Q, Cit, K or a variant thereof), glycine (G), alanine (A) or a variant thereof (e.g., da, 2-aminoisobutyric acid (Aib)); X4 is a hydrophobic amino acid (e.g., leucine (L)), a hydrophilic amino acid (e.g., citrulline (Cit)) or a variant thereof; X5 is a hydrophilic amino acid or a variant thereof; X6 is a hydrophilic amino acid, an amino acid containing an aromatic ring, or its N-methylated amino acid; X7 is an amino acid containing an aromatic ring (e.g., W, F, or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, an N-methylated amino acid, or a variant thereof; X9 is an amino acid containing an aromatic ring (e.g., W or a variant thereof); X10 is absent or is a hydrophilic amino acid (e.g., threonine (T) or a variant thereof); X11 is absent or is a hydrophilic amino acid; and X12 is cysteine (C) or a variant thereof.

[0109] 99. A (cyclic) peptide that has an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide consists of: the sequence of formula (I), X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) or a pharmaceutically acceptable salt thereof, wherein each of X1, X2, X3, X4, X5, X6 and X8 is independently an amino acid; X7 is W1Me or a variant thereof; X9 is W1Me or a variant thereof; each of X10 and X11 is independently absent or is an amino acid; and X12 is cysteine (C) or a variant thereof; and, wherein the peptide is optionally linked to a payload molecule via a linker.

[0110] 100. The (cyclic) peptide according to any one of Examples 97 to 99, wherein the peptide competes for binding to human EphA2 at one or more amino acid residues selected from: Asp53, Met55, Asn57, Met59, Met66, Thr101, Arg103, Phe156, Glu157, Arg159, Val161, Val189, and Ala190.

[0111] 101. The (cyclic) peptide according to Example 100, wherein the peptide competes for binding to human EphA2 at one or more amino acid residues selected from: Asp53, Phe156, and Glu157.

[0112] 102. The (cyclic) peptide according to any one of Examples 97 to 101, wherein the human EphA2 comprises the sequence of SEQ ID NO:276 or SEQ ID NO:277.

[0113] 103. A pharmaceutical composition comprising the peptide according to any one of Examples 1-102 or a salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0114] 104. A conjugate comprising the peptide according to any one of the foregoing examples or a salt thereof, and a substance, wherein the substance is selected from the group consisting of: nucleotides, small molecules, medium-sized molecules (e.g., having a M.W. of about 1,000 - 2,500 Da), large-sized molecules (e.g., having a M.W. > 2,500 Da), polymeric compounds, proteins, peptides, tags, biological fragments, carriers including pharmaceutical compounds, or combinations thereof.

[0115] 105. A method of treating a disease or disorder characterized by overexpression of EphA2, the method comprising administering to a subject the peptide according to any one of Examples 1-102 or a salt thereof, the conjugate according to Example 103, or the pharmaceutical composition according to Example 104.

[0116] 106. The method according to Example 105, wherein the disease or disorder is cancer.

[0117] 107. The method according to Example 106, wherein the cancer is selected from glioblastoma, prostate cancer, lung cancer, breast cancer, gastric cancer, ovarian cancer, bladder cancer, colon cancer, esophageal cancer, multiple myeloma, and fibrosarcoma.

[0118] 108. The method according to claim 106, wherein the cancer is non-small cell lung cancer (NSCLC).

[0119] 109. The method according to embodiment 106, wherein the cancer is triple-negative breast cancer.

[0120] 110. A kit, reagent or composition for determining the expression level of EphA2 in a sample, wherein the kit, reagent or composition comprises a peptide or a salt thereof according to any one of embodiments 1-102, a conjugate according to embodiment 103 or a pharmaceutical composition according to embodiment 104.

[0121] 111. The kit, reagent or composition according to embodiment 110, which is suitable for use in a method for diagnosing a disease or disorder characterized by overexpression or reduced expression of EphA2.

[0122] 112. The kit, reagent or composition according to embodiment 110 or 111, wherein the sample is from a subject suffering from a disease or disorder characterized by overexpression or reduced expression of EphA2.

[0123] 113. Use of the peptide or a salt thereof according to any one of the preceding claims in the manufacture of a medicament for diagnosing and / or treating a disease or disorder characterized by overexpression or reduced expression of EphA2.

[0124] 114. The peptide or a salt thereof according to any one of the preceding embodiments for use in diagnosing and / or treating a disease or disorder characterized by overexpression or reduced expression of EphA2.

[0125] In some embodiments, the peptide of the present technology is an isolated peptide.

[0126] In some embodiments, the peptide of the present technology is a purified peptide.

[0127] However, in all aspects of the present disclosure, the substance or payload molecule excludes any radioactive material. Examples of excluded substances are as follows: radioisotopes, radiopharmaceuticals or any compound having a radioactive component. In all aspects of the present disclosure, the substance further excludes any chelating agent for radioisotope conjugation, whether the chelating agent is directly linked to the peptide or linked to the peptide via a linker. Thus, the complexes, conjugates or PDCs described herein do not cover any compound containing a chelating agent for radioisotope conjugation and do not cover radioisotopes.

[0128] Since the peptide of the present technology has the ability to bind to EphA2, the peptide has the potential to target and transport compounds having a pharmacological effect on EphA2, such as low molecular weight compounds, medium molecular weight compounds, high molecular weight compounds, peptides, proteins, antibodies and nucleic acids.

[0129] Other aspects and features of the present disclosure will become apparent to those of ordinary skill in the art after reading the following description of specific embodiments in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0130] All features of the embodiments described in the present disclosure are not mutually exclusive and can be combined with each other. For example, the elements of one embodiment can be used in another embodiment without further elaboration. The following describes specific embodiments in detail with reference to the accompanying drawings, in which:

[0131] Figure 1 An exemplary PDC of the present disclosure is shown, in which represents a linker, and the peptide covalently linked to the payload represented by a rounded square is shown in the circle.

[0132] Figure 2 A general synthetic scheme A of the macrocyclic peptide I of the present invention is shown.

[0133] Figure 3 A general synthetic scheme B of the macrocyclic peptide II of the present invention is shown.

[0134] Figure 4 A general synthetic scheme C of the macrocyclic peptide III of the present invention is shown.

[0135] Figure 5 A synthetic scheme of PDC_EphA2-00007196-C004 (SEQ ID NO: 224) is shown.

[0136] Figure 6 A synthetic scheme of PDC_EphA2-00007196-C010 (SEQ ID NO: 231) is shown. Figure 6 "bA-MeG-MeG-MeG-MeG-MeG-MeG-MeG-MeG-MeG-MeG" as SEQ ID NO: 279 is disclosed. DETAILED DESCRIPTION

[0137] It should be understood that the following general description and detailed description are merely illustrative and descriptive, and do not limit the technology of the present application. In this specification, unless otherwise specified, the singular forms also include the plural forms. In this specification, unless otherwise specified, "or (or)" means "and / or (and / or)". Further, unless otherwise specified, terms such as "element" or "component" cover both elements and components including a single unit and elements and components including two or more sub-units.

[0138] The headings used in this specification are for structural purposes only and should in no way be construed as limiting the subject matter described. All or portions of the documents cited in this application, including but not limited to patents, patent applications, articles, books, and theses, are hereby expressly incorporated by reference in their entirety or in part from the portions of the documents discussed in this specification.

[0139] Numerical ranges recited herein using endpoint recitations are intended to include all numbers subsumed within that range (e.g., the recitation of 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 4.32, and 5).

[0140] As used herein and in the appended claims, the singular forms "a / an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a medicament" includes a plurality of such medicaments, and reference to "the cell" includes reference to one or more cells (or cell populations) and their equivalent expressions known to those skilled in the art, and so forth. When ranges are used herein for physical properties (e.g., molecular weight) or chemical properties (e.g., chemical formula), all combinations and subcombinations of the ranges and specific embodiments therein are intended to be included.

[0141] The terms "about" or "approximately" may mean within an acceptable error range determined by one of ordinary skill in the art for a particular value, which will depend in part on how the value is measured or determined, i.e., subject to the limitations of the measurement system. For example, in accordance with the practice in the art, "about" may mean within one or more standard deviations. Alternatively, "about" may mean a range up to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, especially for biological systems and methods, the term may mean within an order of magnitude of a value, within 5-fold, or within 2-fold.

[0142] The term "comprising" (and related terms such as "comprise", "comprises", "having", or "including") should be interpreted in an open, inclusive sense, i.e., as "including but not limited to". The term "comprising" (and related terms such as "comprise", "comprises", "having", or "including") is not intended to exclude in other certain embodiments, for example, in embodiments of any substance composition, composition, method, or process, etc., described herein, the case of "consisting of the features" or "consisting essentially of the features".

[0143] "Amino" refers to the –NH2 radical.

[0144] "Cyano" refers to the -CN radical.

[0145] "Nitro" refers to the -NO2 radical.

[0146] "Oxo" refers to the =O radical.

[0147] "Imino" refers to the =N-H radical.

[0148] "Oximino" refers to the =N-OH radical.

[0149] "Hydrazino" refers to the =N-NH2 radical.

[0150] "Hydroxy" refers to the -OH radical.

[0151] "Hydroxyamino" refers to the -NH-OH radical.

[0152] "Acyl" refers to a substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted heterocycloalkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, amide or ester, wherein the carbonyl atom of the carbonyl group is the point of attachment. Unless otherwise expressly stated in the specification, the alkylcarbonyl group, alkenylcarbonyl group, alkynylcarbonyl group, cycloalkylcarbonyl group, amide group or ester group is optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.

[0153] "Alkyl" refers to an optionally substituted straight-chain or optionally substituted branched-chain saturated hydrocarbon monovalent radical. The alkyl group can have from one to about twenty carbon atoms, from one to about ten carbon atoms or from one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl and hexyl, and longer alkyl groups such as heptyl, octyl, etc. Whenever it appears herein, a numerical range such as "C1-C6 alkyl" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but this definition also covers the occurrence of the term "alkyl" without a specified numerical range. In some embodiments, the alkyl is C1-C10 Alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl or C1 alkyl. Unless otherwise explicitly stated in the specification, the alkyl group is optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl is optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, -NO2 or -C≡CH. In some embodiments, the alkyl is optionally substituted by oxo, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, the alkyl is optionally substituted by halogen.

[0154] "Alkylene" refers to a straight-chain or branched-chain divalent hydrocarbon chain. Unless otherwise explicitly stated in the specification, the alkylene group is optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkylene is optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkylene is optionally substituted by oxo, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, the alkylene is optionally substituted by halogen. In some embodiments, the alkylene is -CH2-, -CH2CH2-, -CH2CH2CH2- or -CH2CH(CH3)CH2-. In some embodiments, the alkylene is -CH2-. In some embodiments, the alkylene is -CH2CH2-. In some embodiments, the alkylene is -CH2CH2CH2-.

[0155] "Alkenyl" refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monovalent radical having one or more carbon-carbon double bonds. In some embodiments, the alkenyl group has two to about ten carbon atoms, or two to about six carbon atoms. The group can be in a cis or trans configuration around one or more double bonds and is understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Whenever it appears herein, a numerical range such as "C2-C6 alkenyl" means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but this definition also encompasses the occurrence of the term "alkenyl" without a specified numerical range. In some embodiments, the alkenyl is C2-C 10Alkenyl, C2-C9 alkenyl, C2-C8 alkenyl, C2-C7 alkenyl, C2-C6 alkenyl, C2-C5 alkenyl, C2-C4 alkenyl, C2-C3 alkenyl or C2 alkenyl. Unless otherwise expressly stated in the specification, the alkenyl group is optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl is optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkenyl is optionally substituted by oxo, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, the alkenyl is optionally substituted by halogen.

[0156] The term "alkenylene" or "alkenylene chain" refers to an optionally substituted straight or branched divalent hydrocarbon chain having at least one carbon-carbon double bond that links the remainder of the molecule to a radical group. In some embodiments, the alkenylene is –CH=CH-, -CH2CH=CH- or –CH=CHCH2-. In some embodiments, the alkenylene is –CH=CH-. In some embodiments, the alkenylene is –CH2CH=CH-. In some embodiments, the alkenylene is –CH=CHCH2-.

[0157] "Alkynyl" refers to an optionally substituted straight or optionally substituted branched hydrocarbon monovalent radical having one or more carbon-carbon triple bonds. In some embodiments, the alkynyl group has from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. Whenever it appears herein, a numerical range such as "C2-C6 alkynyl" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but this definition also encompasses the occurrence of the term "alkynyl" without a specified numerical range. In some embodiments, the alkynyl is C2-C 10 Alkynyl, C2-C9 alkynyl, C2-C8 alkynyl, C2-C7 alkynyl, C2-C6 alkynyl, C2-C5 alkynyl, C2-C4 alkynyl, C2-C3 alkynyl or C2 alkynyl. Unless otherwise expressly stated in the specification, the alkynyl group is optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkynyl is optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkynyl is optionally substituted by oxo, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, the alkynyl is optionally substituted by halogen. The term "alkynylene" refers to an optionally substituted straight or optionally substituted branched divalent hydrocarbon having one or more carbon-carbon triple bonds.

[0158] "Alkylamino" refers to a radical having the formula -N(R a )2, where R a is an alkyl radical as defined, or two R a together with the nitrogen atom may form a substituted or unsubstituted C2-C7 heterocycloalkyl ring. Unless otherwise expressly stated in the specification, the alkylamino group may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkylamino is optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkylamino is optionally substituted by oxo, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, the alkylamino is optionally substituted by halogen.

[0159] "Alkoxy" refers to a radical having the formula -OR a where R a is an alkyl radical as defined. Unless otherwise expressly stated in the specification, the alkoxy group may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy is optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkoxy is optionally substituted by oxo, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, the alkoxy is optionally substituted by halogen.

[0160] "Aminoalkyl" refers to an alkyl radical as defined above substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two or three amines. Hydroxyalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl or aminopentyl. In some embodiments, the hydroxyalkyl is aminomethyl.

[0161] The term "aryl" refers to a radical containing at least one aromatic ring, wherein each of the atoms forming the ring is a carbon atom. The aryl group may be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. In some embodiments, the aryl is phenyl. Depending on the structure, the aryl group can be a monovalent radical or a divalent radical (i.e., an arylene group). Unless otherwise expressly stated in the specification, the term "aryl" or the prefix "ar-" (e.g., "aralkyl") is intended to include optionally substituted aryl radicals. In some embodiments, the aryl group includes a partially reduced cycloalkyl group as defined herein (e.g., 1,2-dihydronaphthalene). In some embodiments, the aryl group includes a fully reduced cycloalkyl group as defined herein (e.g., 1,2,3,4-tetrahydronaphthalene). When the aryl contains a cycloalkyl group, the aryl is bonded to the remainder of the molecule through an aromatic ring carbon atom. The aryl radical can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic or tetracyclic) ring system, which may include fused, spiro or bridged ring systems. Unless otherwise expressly stated in the specification, the aryl may be optionally substituted, e.g., by halogen, amino, alkylamino, aminoalkyl, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -S(O)2NH-C1-C6 alkyl, etc. In some embodiments, the aryl is optionally substituted by: halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, -NO2, -S(O)2NH2, -S(O)2NHCH3, -S(O)2NHCH2CH3, -S(O)2NHCH(CH3)2, -S(O)2N(CH3)2 or -S(O)2NHC(CH3)3. In some embodiments, the aryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, the aryl is optionally substituted by halogen. In some embodiments, the aryl is substituted by alkyl, alkenyl, alkynyl, haloalkyl or heteroalkyl, wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl is independently unsubstituted or substituted by halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2 or -NO2.

[0162] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical in which each of the atoms forming the ring (i.e., the backbone atoms) is a carbon atom. In some embodiments, the cycloalkyl is saturated or partially unsaturated. In some embodiments, the cycloalkyl is a spiro or bridged compound. In some embodiments, the cycloalkyl is fused to an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having three to ten carbon atoms, three to eight carbon atoms, three to six carbon atoms, or three to five carbon atoms. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl is cyclopentyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl or cyclohexenyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl. Polycyclic radicals include, for example, adamantyl, 1,2-dihydronaphthyl, 1,4-dihydronaphthyl, tetrainyl, decalinyl, 3,4-dihydronaphthalen-1(2H)-one, spiro[2.2]pentyl, norbornyl, and bis[1.1.1]pentyl. Unless otherwise expressly stated in the specification, cycloalkyl groups may be optionally substituted. Representative cycloalkyls include, but are not limited to, cycloalkyls having three to fifteen carbon atoms (C3-C 15 cycloalkyl), cycloalkyls having three to ten carbon atoms (C3-C 10cycloalkyl), cycloalkyl having three to eight carbon atoms (C3-C8 cycloalkyl), cycloalkyl having three to six carbon atoms (C3-C6 cycloalkyl), cycloalkyl having three to five carbon atoms (C3-C5 cycloalkyl), or cycloalkyl having three to four carbon atoms (C3-C4 cycloalkyl). In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decahydronaphthyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthalene, trans-decahydronaphthalene, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane and 7,7-dimethyl-bicyclo[2.2.1]heptyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise expressly stated in the specification, the cycloalkyl is optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the cycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted by halogen.

[0163] "Halogenated" or "halogen" means bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

[0164] "Haloalkyl" means an alkyl radical as defined above substituted by one or more halogens. In some embodiments, the alkyl is substituted by one, two, or three halogens. In some embodiments, the alkyl is substituted by one, two, three, four, five, or six halogens. Haloalkyls can include, for example, iodoalkyl, bromoalkyl, chloroalkyl, and fluoroalkyl. For example, "fluoroalkyl" means an alkyl radical as defined above substituted by one or more fluorine radicals as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical can be optionally substituted as defined above for alkyl.

[0165] "Heteroalkyl" refers to an alkyl group in which one or more of the skeletal atoms of the alkyl group are selected from non-carbon atoms such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule through a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, where the heteroalkyl consists of 1 to 6 carbon atoms and one or more non-carbon atoms such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof, and where the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls include: –CH2-O-CH2-, –CH2-N(alkyl)-CH2-, –CH2-N(aryl)-CH2-, -OCH2CH2O-, –OCH2CH2OCH2CH2O-, or –OCH2CH2OCH2CH2OCH2CH2O-. Unless otherwise explicitly stated in the specification, the heteroalkyl is optionally substituted, e.g., by oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted by halogen.

[0166] As used herein, "heteroalkylene" refers to a divalent heteroalkyl group. Examples of such heteroalkylenes are, for example, -CH2-O-CH2-, -CH2-N(alkyl)-CH2-, -CH2-N(aryl)-CH2-, -OCH2CH2O-, -OCH2CH2OCH2CH2O-, or -OCH2CH2OCH2CH2OCH2CH2O-.

[0167] The term "heterocycloalkyl" refers to a cycloalkyl group that includes at least one heteroatom (e.g., a heteroatom selected from nitrogen, oxygen, and sulfur). Unless otherwise expressly stated in the specification, a heterocycloalkyl radical may be a monocyclic or bicyclic ring system, which may include fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon, or sulfur atoms in the heterocyclic group may optionally be oxidized. The nitrogen atom may optionally be quaternized. The heterocycloalkyl radical is partially saturated or fully saturated. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thieno[1,3]dithianyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidone, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl. The term "heterocycloalkyl" also includes all cyclic forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocycloalkyl has 2 to 12 carbon atoms in the ring. In some embodiments, heterocycloalkyl has 2 to 10 carbon atoms in the ring. In some embodiments, heterocycloalkyl has 2 to 10 carbon atoms and 1 or 2 N atoms in the ring. In some embodiments, heterocycloalkyl has 2 to 10 carbon atoms and 3 or 4 N atoms in the ring. In some embodiments, heterocycloalkyl has 2 to 12 carbons, 0-2 N atoms, 0-2 O atoms, 0-2 P atoms, and 0-1 S atom in the ring. In some embodiments, heterocycloalkyl has 2 to 12 carbons, 1-3 N atoms, 0-1 O atom, and 0-1 S atom in the ring. It should be understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is different from the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). Unless otherwise expressly stated in the specification, heterocycloalkyl is optionally substituted, e.g., by oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heterocycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heterocycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heterocycloalkyl is optionally substituted by halogen.

[0168] "Heteroaryl" refers to a radical of a ring system containing one or more carbon atoms and one or more ring heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, heteroaryl is monocyclic, bicyclic, or polycyclic. Illustrative examples of monocyclic heteroaryl include pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizinyl, indolyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, purinyl, quinazolinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, and pteridinyl. Illustrative examples of monocyclic heteroaryl include pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Illustrative examples of bicyclic heteroaryl include indolizinyl, indolyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, purinyl, quinazolinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, and pteridinyl. In some embodiments, heteroaryl is pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl, or furyl. In some embodiments, heteroaryl contains 0-6 N atoms in the ring. In some embodiments, heteroaryl contains 1-4 N atoms in the ring. In some embodiments, heteroaryl contains 4-6 N atoms in the ring. In some embodiments, heteroaryl contains 0-4 N atoms, 0-1 O atom, 0-1 P atom, and 0-1 S atom in the ring. In some embodiments, heteroaryl contains 1-4 N atoms, 0-1 O atom, and 0-1 S atom in the ring. In some embodiments, heteroaryl is a C1-C9 heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is a C6-C9 heteroaryl. In some embodiments, the heteroaryl group includes a partially reduced cycloalkyl or heterocycloalkyl group as defined herein (e.g., 7,8-dihydroquinoline). In some embodiments, heteroaryl includes a fully reduced cycloalkyl or heterocycloalkyl group as defined herein (e.g., 5,6,7,8-tetrahydroquinoline). When heteroaryl contains a cycloalkyl or heterocycloalkyl group, the heteroaryl is bonded to the rest of the molecule through a heteroaromatic ring carbon or heteroatom. The heteroaryl radical can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which may include fused, spiro, or bridged ring systems. Unless otherwise expressly stated in the specification, heteroaryl is optionally substituted, e.g., by halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.In some embodiments, the heteroaryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, the heteroaryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, the heteroaryl is optionally substituted by halogen.

[0169] The term "moiety" refers to a particular segment or functional group of a molecule. A chemical moiety is generally considered to be a chemical entity that is incorporated into or appended to a molecule.

[0170] As used herein, the terms "treat", "prevent", "ameliorate" and "inhibit" and words derived therefrom do not necessarily mean 100% or complete treatment, prevention, amelioration or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration and inhibition that are considered by those of ordinary skill in the art to have potential benefit or therapeutic effect. In this regard, the disclosed methods can provide any amount and any level of treatment, prevention, amelioration or inhibition of a disorder in a mammal. For example, a disorder (including its symptoms or conditions) can be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20% or about 10%. In addition, the treatment, prevention, amelioration or inhibition provided by the methods disclosed herein can include treating, preventing, ameliorating or inhibiting one or more conditions or symptoms of a disorder (e.g., cancer or an inflammatory disease).

[0171] In certain embodiments, "treatment" includes the concept of "mitigation", which refers to reducing the frequency or severity of the occurrence or recurrence of any symptoms or other adverse effects associated with a disorder and / or related side effects. In certain embodiments, the term "treatment" also encompasses the concept of "management", which refers to reducing the severity of a particular disease or disorder in a patient or delaying its recurrence, e.g., prolonging the remission period of a patient already suffering from the disease.

[0172] In certain embodiments, the terms "prevent" or "preventing" in relation to a disease or disorder can refer to a compound in a statistical sample that reduces the occurrence of a disorder or condition in a treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to an untreated control sample.

[0173] The term "therapeutically effective amount" as used herein refers to an amount that is effective to achieve the desired therapeutic result at the necessary dosage and duration. The therapeutically effective amount of a composition may vary according to factors such as the individual condition, age, sex and weight, as well as the ability of the protein to elicit the desired response in the individual. A therapeutically effective amount can also be an amount that exceeds any toxic or harmful effects of the composition that would have a beneficial effect on the treatment.

[0174] The term "optional" or "optionally" means that the subsequent described event or circumstance may or may not occur, and the description includes the case where the event or circumstance occurs and the case where it does not occur. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. Further, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F) or substituted at any level between fully substituted and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.).

[0175] As used herein, "substituent" means a positional variable on a core molecular atom that substitutes at a specified atomic position, replacing one or more hydrogens on the specified atom, provided that the normal valence of the specified atom is not exceeded and the substitution results in a stable compound. Such combinations are permitted only if the combination of substituents and / or variables can form a stable compound. One of ordinary skill in the art should note that any carbon atom and heteroatom whose valence as described or shown herein appears to be unsatisfied are assumed to have a sufficient number of one or more hydrogen atoms to satisfy the described or shown valence. In some cases, one or more substituents having a double bond (e.g., "oxo" or "=O") as an attachment point in the substituent group may be described, shown or listed herein, where the structure may only show a single bond as the attachment point to the core structure. One of skill in the art should understand that although only a single bond is shown, the double bond is intended for these substituents.

[0176] For the purposes of this disclosure, a "substitution" event of an amino acid or amino sequence is not considered two separate events of a deletion plus an addition. Thus, to avoid doubt, by way of example, sequence variations of "up to two deletions, substitutions and / or additions" include one deletion and one substitution, one deletion and one addition (at different positions), one substitution and one addition, only one deletion, only one substitution, only one addition, two deletions, two substitutions, two additions, etc. The deletion, addition or substitution position may be at one or both ends of the peptide or in the middle of the peptide.

[0177] The term "optionally substituted" or "substituted" means that the recited group is optionally substituted by one or more additional groups, which are independently selected from D, halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone and aryl sulfone. In some other embodiments, the optional substituents are independently selected from D, halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4alkyl), -C(=O)NH2, -C(=O)NH(C1-C4alkyl), -C(=O)N(C1-C4alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4alkyl), -S(=O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, -SC1-C4alkyl, -S(=O)C1-C4alkyl and -S(=O)2C1-C4alkyl. In some embodiments, the optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -NH(cyclopropyl), -CH3, -CH2CH3, -CF3, -OCH3 and -OCF3. In some embodiments, the substituted group is substituted by one or two of the foregoing groups. In some embodiments, the optional substituents on aliphatic carbon atoms (acyclic or cyclic) include oxo (=O). When indicating the number of substituents, the term "one or more" means from one substituent to the highest possible number of substitutions, i.e., replacement of one hydrogen until all hydrogens are replaced by substituents.

[0178] The term "unsubstituted" means that the designated group bears no substituents.

[0179] Certain compounds described herein may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of this disclosure.

[0180] Unless otherwise specified, the structures depicted herein also mean to include all stereochemical forms of the structure; i.e., the R and S configurations of each asymmetric center. Accordingly, single stereoisomers as well as enantiomeric and diastereomeric mixtures of the compounds of the invention are within the scope of this disclosure.

[0181] As used herein, the term "peptide" refers to a compound comprising two or more amino acids. The peptides described herein may contain one or more non-natural amino acids. The term "peptide" also encompasses peptidomimetics. In this disclosure, the term "amino acid" is used in its broadest sense and includes not only natural amino acids but also their derivatives and artificial amino acids. For example, the term "amino acid" encompasses non-natural amino acids.

[0182] As used herein, the term "non-natural amino acid" refers to an amino acid other than the 20 standard amino acids. The 20 standard amino acids are alanine (ala or A), arginine (arg or R), asparagine (asn or N), aspartic acid (asp or D), cysteine (cys or C), glutamine (gln or Q), glutamic acid (glu or E), glycine (gly or G), histidine (his or H), isoleucine (ile or I), leucine (leu or L), lysine (lys or K), methionine (met or M), phenylalanine (phe or F), proline (pro or P), serine (ser or S), threonine (thr or T), tryptophan (trp or W), tyrosine (tyr or Y), and valine (val or V).

[0183] As used herein, the term "protein" refers to a polypeptide (i.e., a string of at least 3 amino acids linked to each other by peptide bonds). A protein may contain moieties other than amino acids (e.g., it may be a glycoprotein, a proteoglycan, etc.), and / or may be processed or modified in other ways. A protein may be a complete polypeptide produced by a cell and / or active in a cell (with or without a signal sequence). In some embodiments, the protein is or comprises a characteristic moiety, such as a polypeptide produced by a cell and / or active in a cell. A protein may contain more than one polypeptide chain. For example, the polypeptide chains may be linked by one or more disulfide bonds or associated in other ways.

[0184] The term "peptidomimetic" or "mimetic" refers to a bioactive compound that mimics the biological activity of a peptide or protein but is no longer entirely a peptide in chemical nature. For example, they may contain non-peptide bonds (i.e., bonds other than amide bonds between amino acids). As used herein, the term peptidomimetic is used in a broader sense to include molecules that are no longer entirely peptides in nature, such as pseudopeptides, semipeptides, and peptoids. Whether fully or partially non-peptide, the peptidomimetics described herein can provide a spatial arrangement of reactive chemical moieties that is very similar to the three-dimensional arrangement of the active groups in the subject amino acid sequence or the subject molecule on which the peptidomimetic is based. Due to this similar active site geometry, peptidomimetics can have an effect on biological systems similar to the biological activity of the subject entity.

[0185] In some embodiments, the peptidomimetic is substantially similar to the subject amino acid sequence or subject molecule upon which the peptidomimetic is based in terms of three-dimensional shape and biological activity. Examples are described in the paper “Tritiated D-ala1-Peptide TBinding [Tritiated D-ala1-Peptide T Binding]”, Smith C.S. et al., Drug Development Res. [Drug Development Research], 15, pp. 371-379 (1988). A second approach is to modify the cyclic structure for stability, such as imides and lactams between the N-to-C chains (Ede et al. in Smith and Rivier (eds.) “Peptides: Chemistry and Biology [Peptides: Chemistry and Biology]”, Escom, Leiden (1991), pp. 268-270). Examples thereof are provided in conformationally restricted thymopentin compounds, such as the compounds disclosed in US 4457489. A third approach is to replace peptide bonds in the subject entity with pseudopeptide bonds that confer resistance to proteolysis.

[0186] The ranges provided herein are understood to be shorthand for all values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, and all intermediate decimal values between the integers mentioned above, such as 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, “nested sub-ranges” extending from either endpoint of the range are specifically contemplated. For example, nested sub-ranges of the exemplary range of 1 to 50 can include 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.

[0187] As used herein, C1-C x (or C 1-x ) includes C1-C2, C1-C3... C1-C xBy way of example only, a group designated as "C1-C4" indicates the presence of one to four carbon atoms in that portion, i.e., the group contains 1, 2, 3, or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" indicates the presence of one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from the following: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Additionally, for example, C0-C2 alkylene includes a direct bond, -CH2-, and -CH2CH2- linkages.

[0188] As used herein, the term "cyclized" or "cyclizing" means that two amino acids that are at least one amino acid apart from each other in a peptide bind directly or indirectly to each other to form a cyclic structure in the molecule. In some cases, the two amino acids are linked by a linker or the like.

[0189] The term "subject" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other ape and monkey species; farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; experimental animals including rodents such as rats, mice, and guinea pigs, etc. In one aspect, the mammal is a companion animal such as a dog or a cat. In one aspect, the mammal is a human.

[0190] As used herein, the term "therapeutically effective amount" means an amount that is effective at a dosage to achieve the desired therapeutic result. The therapeutically effective amount of a composition may vary depending on factors such as the individual condition (e.g., age, sex, and weight), the conjugate, and the method of administration (e.g., oral or parenteral).

[0191] The percent sequence identity can be calculated using a computer program or direct sequence comparison. Preferred computer program methods for determining identity between two sequences include, but are not limited to, the GCG program package, FASTA, BLASTP, and TBLASTN (see, e.g., D.W. Mount, 2001, Bioinformatics: Sequence and Genome Analysis, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY). The BLASTP and TBLASTN programs are publicly available from NCBI and other sources. The Smith Waterman algorithm can also be used to determine the percent identity. Exemplary parameters for amino acid sequence comparison include the following: 1) the Needleman and Wunsch algorithm (J. Mol. Biol., 48:443-453 (1970)); 2) the BLOSSUM62 comparison matrix of Hentikoff and Hentikoff (Proc. Nat. Acad. Sci. USA, 89:10915-10919 (1992)); 3) gap penalty = 12; and 4) gap length penalty = 4. Programs using these parameters are publicly available as the "gap" program (Genetics Computer Group, Madison, WI). The above parameters are the default parameters for polypeptide comparison (no penalty for terminal gaps). Alternatively, polypeptide sequence identity can be calculated using the following equation: percent identity = (number of identical residues) / (length of alignment of amino acid residues) * 100. For this calculation, the length of the alignment includes internal gaps, but not terminal gaps.

[0192] It should be understood that certain features of the present disclosure that are described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, the various features of the present disclosure that are described in the context of a single embodiment for brevity may also be provided separately or in any suitable sub-combination. For example, the conjugates of the present disclosure may comprise any of the peptide ligands described herein (e.g., peptide ligands having formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), or (Ic) or the peptide ligands of Table 1), any of the payload molecules described herein, optionally a linker described herein (e.g., a linker having formula (II-1), (II-1a), (II-1b) or (II-2)), and optionally a payload molecule described herein. As another example, a peptide having formula (I) (or any other formula, such as (III-1) and (III-2)) may comprise the amino acids X1 to X12 as described herein, and any combination of the exemplified amino acids is encompassed in the present disclosure (even if, in some cases, they are described in the context of separate embodiments).

[0193] Unless otherwise specifically defined, the terms used in this specification related to analytical chemistry, synthetic organic chemistry, medicinal chemistry, and pharmaceutical chemistry, as well as the procedures and techniques thereof, are well-known and commonly used in the art. Standard techniques may be used for chemical synthesis and chemical analysis. Those of the definitions in these techniques and procedures may be found in, for example, "K.J. Jensen, P.T. Shelton, S.L. Pedersen, Peptide Synthesis and Applications [Peptide Synthesis and Applications], 2nd Edition, Springer, 2013", etc., and these are incorporated herein by reference for all purposes. All patents, applications, published applications, and other publications, as well as other data cited throughout the disclosure, are incorporated herein by reference when permitted. Abbreviations:

[0194] Unless otherwise expressly stated in this specification, the following abbreviations will be used with the following meanings: Alloc allyloxycarbonyl aq. aqueous Biotin-OSu biotin N-hydroxysuccinimide ester (CAS 35013-72-0) Boc tert-butoxycarbonyl ClAcOH chloroacetic acid ClAcOSu 2-chloroacetic acid N-succinimidyl ester (CAS 27243-15-8) DCM Dichloromethane (CAS 75-09-2) DIC N,N′-Diisopropylcarbodiimide (CAS 693-13-0) DIPEA, DIEA N,N-Diisopropylethylamine (CAS 7087-68-5) DMF N,N-Dimethylformamide (CAS 68-12-2) DODT 2,2′-(Ethylenedioxy)diethanethiol (CAS14970-87-7) EDCI-HCl N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (CAS25952-53-8) eq Equivalent Et Ethyl Et3N, TEA Triethylamine (CAS121-44-8) Fmoc 9-Fluorenylmethoxycarbonyl hr Hour HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (CAS148893-10-1) HOSu N-Hydroxysuccinimide (CAS 6066-82-6) iPrOH / IPA Isopropyl alcohol M Mole min Minute NHS N-Hydroxysuccinimide (CAS 6066-82-6) NMP N-Methylpyrrolidone (CAS 872-50-4) Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium(0) (CAS:14221-01-3) Ph Phenyl rpm Revolutions per minute rt Room temperature SPPS Solid-phase peptide synthesis Su Succinimide SulfoCy5 Sulfo-Cyanine 5 tert Tertiary TFA Trifluoroacetic acid (CAS 76-05-1) TIS Triisopropylsilane (CAS 6485-79-6) TR Retention time Trt Triphenylmethyl. Peptide:

[0195] In one aspect, the present disclosure relates to a peptide (e.g., a binding peptide) having an affinity for ephrin type-A receptor 2 (EphA2). EphA2 can be mammalian EphA2. EphA2 can be human EphA2. EphA2 can be wild-type or mutant EphA2. In some embodiments, the conjugate of the present disclosure comprises two or more peptides, which can be the same or different. The peptides can be linear or cyclic. In some embodiments, the peptide is monocyclic. The peptide can comprise any suitable number of amino acid residues. In some embodiments, the peptide comprises 5 to 50, 6 to 40, 7 to 30, 8 to 25, 12 to 25, or 9 to 20 amino acid residues. In some embodiments, the peptide comprises 5 to 14 amino acid residues. In some embodiments, the peptide comprises 7 to 12 amino acid residues. In some embodiments, the peptide comprises 8 to 12 amino acid residues. In some embodiments, the peptide comprises 8 to 10 amino acid residues. In some embodiments, the peptide comprises 7 to 13 amino acid residues. In some embodiments, the peptide comprises 12 to 15 amino acid residues. In some embodiments, the peptide comprises 13 to 14 amino acid residues. In some embodiments, the peptide comprises 6 amino acid residues. In some embodiments, the peptide comprises 7 amino acid residues. In some embodiments, the peptide comprises 8 amino acid residues. In some embodiments, the peptide comprises 9 amino acid residues. In some embodiments, the peptide comprises 10 amino acid residues. In some embodiments, the peptide comprises 11 amino acid residues. In some embodiments, the peptide comprises 12 amino acid residues. In some embodiments, the peptide comprises 13 amino acid residues. In some embodiments, the peptide comprises 14 amino acid residues. In some embodiments, the peptide comprises 15 amino acid residues. In some embodiments, the peptide comprises 16 amino acid residues. In some embodiments, the peptide consists of 6 amino acid residues. In some embodiments, the peptide consists of 7 amino acid residues. In some embodiments, the peptide consists of 8 amino acid residues. In some embodiments, the peptide consists of 9 amino acid residues. In some embodiments, the peptide consists of 10 amino acid residues. In some embodiments, the peptide consists of 11 amino acid residues. In some embodiments, the peptide consists of 12 amino acid residues. In some embodiments, the peptide consists of 13 amino acid residues. In some embodiments, the peptide consists of 14 amino acid residues. In some embodiments, the peptide consists of 15 amino acid residues. In some embodiments, the peptide consists of 16 amino acid residues. In some embodiments, the conjugate comprises a monocyclic peptide having 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. The peptides described herein can be binding peptides that bind EphA2. In some embodiments, the binding peptide consists of 6 to 20 amino acid residues. In some embodiments, the binding peptide consists of 7 to 12 amino acid residues. In some embodiments, the binding peptide consists of 10 to 12 amino acid residues. In some embodiments, the binding peptide consists of 8 to 12 amino acid residues.In some embodiments, the binding peptide is monocyclic. In some embodiments, the peptides of the present technology are isolated peptides. In some embodiments, the peptides of the present technology are purified peptides.

[0196] In one aspect, described herein is a peptide (e.g., a cyclic peptide) that has an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide comprises an amino acid sequence that includes one or several (e.g., 1 - 6) deletions, substitutions, and / or additions of the following amino acids: the amino acid sequence of SEQ ID NO:1 da-MeF-N-L-Hgl-MeF-W1Me-V-W1Me-T-E-C (SEQ ID NO:1). Or a pharmaceutically acceptable salt thereof. Optionally, the (cyclic) peptide consists of 10 to 12 amino acid residues.

[0197] In some embodiments, the (cyclic) peptide consists of 10 to 12 amino acid residues.

[0198] In some embodiments, the peptide comprises an amino acid sequence that includes a total of at most 6 deletions, substitutions, and / or additions of one or several amino acids of the amino acids of SEQ ID NO:1. In some embodiments, the peptide comprises an amino acid sequence that includes a total of at most 5 deletions, substitutions, and / or additions of one or several amino acids of the amino acids of SEQ ID NO:1. In some embodiments, the peptide comprises an amino acid sequence that includes a total of at most 4 deletions, substitutions, and / or additions of one or several amino acids of the amino acids of SEQ ID NO:1. In some embodiments, the peptide comprises an amino acid sequence that includes a total of at most 3 deletions, substitutions, and / or additions of one or several amino acids of the amino acids of SEQ ID NO:1. In some embodiments, the peptide comprises an amino acid sequence that includes a total of at most 2 deletions, substitutions, and / or additions of one or several amino acids of the amino acids of SEQ ID NO:1. In some embodiments, the peptide comprises an amino acid sequence that includes a total of at most 1 deletion, substitution, and / or addition of one or several amino acids of the amino acids of SEQ ID NO:1. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. The positions of the deletions, additions, or substitutions can be at one or both ends of the peptide, or in the middle of the peptide.

[0199] In some embodiments, the peptide comprises an amino acid sequence in which 1 - 5 amino acids selected from the group consisting of: N at position 3, L at position 4, Hgl at position 5, MeF at position 6, T at position 10, and E at position 11 in SEQ ID NO:1 are deleted in the peptide. In some embodiments, the peptide comprises an amino acid sequence in which 1, 2, 3, 4, or 5 amino acids selected from the group consisting of: N at position 3, L at position 4, Hgl at position 5, MeF at position 6, T at position 10, and E at position 11 in SEQ ID NO:1 are deleted in the peptide. In some embodiments, N at position 3 is deleted. In some embodiments, L at position 4 is deleted. In some embodiments, Hgl at position 5 is deleted. In some embodiments, MeF at position 6 is deleted. In some embodiments, E at position 11 is deleted. In some embodiments, the peptide comprises an amino acid sequence in which 1 - 5 amino acids selected from the group consisting of the amino acids at positions 3, 4, 5, 6, 10, and 11 of SEQID NO:1 are deleted in the peptide. In some embodiments, the peptide comprises an amino acid sequence in which 1, 2, 3, 4, or 5 amino acids selected from the group consisting of the amino acids at positions 3, 4, 5, 6, 10, and 11 of SEQ ID NO:1 are deleted in the peptide. In some embodiments, the amino acid at position 3 is deleted. In some embodiments, the amino acid at position 4 is deleted. In some embodiments, the amino acid at position 5 is deleted. In some embodiments, the amino acid at position 6 is deleted. In some embodiments, the amino acid at position 10 is deleted. In some embodiments, the amino acid at position 11 is deleted. In certain embodiments, the peptide has a deletion of 1 - 5 amino acids of SEQ ID NO:1 and no additional residues are added. In certain embodiments, the peptide has a deletion of 1 - 5 amino acids of SEQ ID NO:1 and no additional residues are substituted. In certain embodiments, the peptide has a deletion of 1 - 5 amino acids of SEQ ID NO:1 and no additional residues are added or substituted. In certain embodiments, the peptide has a deletion of 1 - 5 amino acid residues of SEQ ID NO:1 and no residues are added. In certain embodiments, the peptide has a deletion of 1 - 5 amino acid residues of SEQ ID NO:1 and no residues are substituted. In certain embodiments, the peptide has a deletion of 1 - 5 amino acid residues of SEQ ID NO:1 and no residues are added or substituted.

[0200] In one aspect, described herein is a peptide (e.g., a cyclic peptide) that has an affinity for ephrin type - A receptor 2 (EphA2), wherein the peptide has an amino acid sequence according to formula (I), or a pharmaceutically acceptable salt thereof, X1 - X2 - X3 - X4 - X5 - X6 - X7 - X8 - X9 - X10 - X11 - X12 Formula (I) X1 is an amino acid; X2 is an amino acid containing an aromatic ring, its N-methylated amino acid, or its variant; X3 is a hydrophilic amino acid (e.g., N, Q, Cit, K, or its variant), glycine (G), alanine (A), or its variant (e.g., da, 2-aminoisobutyric acid (Aib)); X4 is a hydrophobic amino acid (e.g., leucine (L)), a hydrophilic amino acid (e.g., citrulline (Cit)), or its variant; X5 is a hydrophilic amino acid or its variant; X6 is a hydrophilic amino acid, an amino acid containing an aromatic ring, or its N-methylated amino acid; X7 is an amino acid containing an aromatic ring (e.g., W, F, or its variant); X8 is a hydrophobic amino acid, a hydrophilic amino acid, an N-methylated amino acid, or its variant; X9 is an amino acid containing an aromatic ring (e.g., W or its variant); X10 is absent or is a hydrophilic amino acid (e.g., threonine (T) or its variant); X11 is absent or is a hydrophilic amino acid; and X12 is cysteine (C) or its variant.

[0201] In certain embodiments, X3 is a hydrophilic amino acid. In certain embodiments, X3 is an amino acid containing a charged side chain (e.g., K or its variant), an amino acid containing a polar uncharged side chain (e.g., Q, Cit, N, or its variant), or G, A, or its variant. In certain embodiments, X4 is a hydrophobic amino acid. In certain embodiments, X4 is an amino acid containing a hydrophobic side chain (e.g., L), an amino acid containing a polar uncharged side chain (e.g., Cit or its variant). In certain embodiments, X5 is a hydrophilic amino acid. In certain embodiments, X5 is an amino acid containing a charged side chain (e.g., E, Hgl, D, or its variant) or an amino acid containing a polar uncharged side chain (e.g., Q, Cit, Hgn, N, or its variant). In certain embodiments, X6 is a hydrophilic amino acid. In certain embodiments, X6 is an amino acid containing a charged side chain (e.g., E, Hgl, D, or its variant) or an amino acid containing a polar uncharged side chain (e.g., Q, Cit, Hgn, N, or its variant). In certain embodiments, X11 is a hydrophilic amino acid. In certain embodiments, X11 is an amino acid containing a charged side chain (e.g., E, Hgl, D, R, hArg, K, or its variant) or an amino acid containing a polar uncharged side chain (e.g., Q, Cit, Hgn, N, or its variant).

[0202] In one aspect, the present disclosure describes a peptide that has an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide has an amino acid sequence according to formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is an amino acid; X2 is F, or a variant thereof, wherein the unsubstituted phenyl ring of F is replaced with: (i) a phenyl ring substituted with 1 or 2 substituents each independently selected from: -OH, -CN, -C 1-3 alkyl (e.g., -CH3), or (ii) a 6-membered heteroaryl ring optionally substituted with 1 or 2 substituents each independently selected from: –OH, -CN, -C 1-3 alkyl (e.g., -CH3), wherein the F or its structural variant is optionally N-methylated; X3 is a hydrophilic amino acid (e.g., N, Q, Cit, K or a variant thereof), G, Aib, Hgn, Ala, or a variant thereof (e.g., da); X4 is a hydrophobic amino acid (e.g., an amino acid having 4 or more carbon atoms in a side chain comprising a straight, branched or cyclic carbon chain), and wherein X4 is optionally N-methylated (e.g., Cit or a variant thereof); X5 is an amino acid (e.g., a hydrophilic amino acid; or an amino acid having a functional side chain (e.g., non-glycine)); X6 is its N-methylated amino acid; X7 is W, Y, or a variant thereof (e.g., an amino acid having a 6-membered aryl or heteroaryl, or a 9- or 10-membered bicyclic aryl or heteroaryl attached to the α-carbon through a carbon (e.g., a methylene group), wherein the 6-membered, 9- and 10-membered heteroaryl has one heteroatom (e.g., N), and wherein the 6-membered, 9- and 10-membered aryl or heteroaryl is optionally substituted with 1 or 2 substituents independently selected from: –CH3, -ethyl, -Cl and -F); X8 is an amino acid having –H on the α-amino group; X9 is W or Y or a variant thereof; (e.g., W or a variant thereof); X10 is absent, or a polar amino acid (e.g., T or a variant thereof); X11 is absent, or is an amino acid (e.g., a hydrophilic amino acid; Dab, Dap, R, E or a variant thereof; or an amino acid with a functional side chain (e.g., other than glycine)); and X12 is C or a variant thereof.

[0203] In some embodiments of formula (I), both X10 and X11 are present. In some embodiments of formula (I), both X10 and X11 are absent.

[0204] In some embodiments, described herein is a peptide (e.g., a cyclic peptide) of formula (I) or a pharmaceutically acceptable salt thereof, wherein X1 is an amino acid (e.g., a D-amino acid); X2 is F or a variant thereof, Y or a variant thereof, or W or a variant thereof, or an N-methylated amino acid thereof; X3 is absent, N, Q, Cit or a variant thereof, G, Aib, Hgn, K or a variant thereof, Ala or da; X4 is absent, G substituted with a linear or branched C 1-5 alkyl, A substituted with a C 3-7 cycloalkyl, or Cit or a variant thereof; X5 is absent, a hydrophilic amino acid or an amino acid with a functional side chain (e.g., Dab, Dap, R, E), wherein the hydrophilic amino acid comprises an L-amino acid containing: -NH2, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2 or -NHC(O)CH3; X6 is absent, a hydrophilic amino acid, F or a variant thereof, Y or a variant thereof, W or a variant thereof, or an N-methylated amino acid thereof, wherein the hydrophilic amino acid comprises a substituent selected from the group consisting of: -C(O)OH, -C(O)NH2 and -NHC(O)CH3; X7 is F or a variant thereof, or W or a variant thereof; X8 is G substituted with one or two linear or branched C 1-5 alkyl, G substituted with a C 3-7 cycloalkyl, A substituted with a C 3-7 cycloalkyl, or a hydrophilic amino acid, wherein the hydrophilic amino acid comprises an L-amino acid containing: -NH2, one or more -OH, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2, -NHC(O)CH3; or the hydrophilic amino acid comprises a zwitterion; X9 is F or a variant thereof, or W or a variant thereof; X10 is absent, Q, Hgn, S or a variant thereof, T or a variant thereof (e.g., optionally substituted with a linear or branched C1-5 an alkyl-substituted T, K or a variant thereof, Cit or a variant thereof, or an L-amino acid substituted with -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2 or -NHC(O)CH3; X11 is absent, E, Hgn, R or a variant thereof, Cit or a variant thereof, Hgl, K or a variant thereof, D, N or Q; and X12 is C or a variant thereof.

[0205] In some embodiments of the peptide of formula (I) or a pharmaceutically acceptable salt thereof, wherein: X1 is da, df3CON, dkCOpipzaa, dahp, dDab-NH2-Ph3-SO2F, dDap-NH2-Ph3-SO2F, dDap-NH2-Ph4-SO2F, dCit, Aib, G, norvaline, norleucine or dhAla; X2 is MeF, Me3Py, MeF3CON, MeF3F, Me4Py, MeY(Me) or an N-methylated amino acid thereof; X3 is absent, N, Q, Cit, G, Aib, Hgn, hCit, norCit, LysAc, OrnAc, Ala or da; X4 is L, Cbg, Chg, Cba, Cha, Ahx, Dahp, Cit, I, V, norleucine or norvaline; X5 is Hgl, Hgn, Dab, Dap, DabAc, DapAc, R, hArg, E or D; X6 is absent, MeF, MeE, Me3Py, Me4Py, MeF4F, MeF4F, MeF4C or MeY; X7 is W1Me, W1Me7Cl, W1Me7N, W, F, 7-AzaTrp, W7Me or W1Et; X8 is V, KCOpipzaa, Cit, Q-reduced glucosamine, hCit, Aib, norleucine or norvaline; X9 is W1Me, W1Me7Cl, W1Me7N, F23dMe, W1Et, W7Me, W, F or 7-AzaTrp; X10 is absent, T, Q, S, Hgn, α-methylserine, hSer, hThr, N, OrnAc, LysAc, Cit or hCit; X11 is absent, E, Hgn, R, hArg, Cit, hCit, Hgl, Orn, D, N, Q, DapAc, OrnAc, DabAc, norCit; and X12 is C, hCys, CdMe, C3RMe, C3SMe, selenocysteine, dc, or penicillamine.

[0206] In some embodiments of the peptide of formula (I) or a pharmaceutically acceptable salt thereof, X7 is W1Me or a variant thereof; and X9 is W1Me or a variant thereof.

[0207] In some embodiments of the peptide of formula (I) or a pharmaceutically acceptable salt thereof, wherein: X7 is W1Me, W1MeCl, W1MeBr, Nal1, Nal2, W1Et, 3Bzf, 3Bzt, F23dC, W1Me7N, or F23dMe; X8 is V, KCOpipzaa, N, Cit, hCit, KAc, DapAc, OrnAc, A, T, alT, Aib, Alb, Q-reduced glucosamine, Hgl, Q, E, Hgn, or K; and X9 is W1Me, Nal1, W1Et, Nal21N, 3Bzf, 3Bzt, Nal18N, F23dMe, or F23dC.

[0208] In some embodiments of the peptide of formula (I) or a pharmaceutically acceptable salt thereof, wherein: X7 is W1Me; X8 is V; and, X9 is W1Me.

[0209] In one aspect, the peptides described herein are peptides (e.g., cyclic peptides) having an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide has an amino acid sequence according to formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) Wherein, X1 is any amino acid (e.g., D-amino acid); X2 is an amino acid containing an aromatic ring or a substituted, N-methylated amino acid, or a substitution thereof; X3 is absent, N, or a substitution thereof; X4 is absent, any hydrophobic amino acid, or a substitution thereof; X5 is absent, a hydrophilic amino acid, or a substitution thereof, or an amino acid having a functional side chain (e.g., Dab, Dap, K); X6 is absent, a hydrophilic amino acid, an amino acid having an aromatic ring, its N-methylated amino acid, or its substituent; X7 is W or its substituent; X8 is V, a hydrophilic amino acid, its substituted, N-methylated amino acid, or an amino acid having a functional side chain; X9 is W or its substitution; X10 is absent, T or its substitution; X11 is absent, any hydrophilic amino acid, or an amino acid having a functional side chain; and X12 is C or its substitution.

[0210] In some embodiments, described herein is a peptide (e.g., a cyclic peptide) having an amino acid sequence according to formula (I) or a pharmaceutically acceptable salt thereof, wherein X1 is any amino acid (e.g., a D-amino acid); X2 is an amino acid containing an aromatic ring, its variant, or its N-methylated amino acid; X3 is absent, N or its variant; X4 is absent, any hydrophobic amino acid, or its variant; X5 is absent, a hydrophilic amino acid, its variant, or an amino acid having a functional side chain (e.g., Dab, Dap, K); X6 is absent, a hydrophilic amino acid, an amino acid having an aromatic ring, or its N-methylated amino acid; X7 is W or its variant; X8 is V, a hydrophilic amino acid, its variant, N-methylated amino acid, or an amino acid having a functional side chain; X9 is W or its variant; X10 is absent, T or its variant; X11 is absent, any hydrophilic amino acid, or an amino acid having a functional side chain; and X12 is C or its variant.

[0211] In some embodiments, described herein is a peptide having formula (I) or a pharmaceutically acceptable salt thereof, wherein X1 is any amino acid; X2 is an amino acid containing an aromatic ring, or its N-methylated amino acid; X3 is absent, a hydrophilic amino acid (e.g., N, Q, Cit, K or its variant), G, Aib, Hgn, or Ala or its variant (e.g., da); X4 is absent, a hydrophobic amino acid, or a hydrophilic amino acid (e.g., Cit or its variant); X5 is absent, a hydrophilic amino acid, or an amino acid having a functional side chain; X6 is absent, a hydrophilic amino acid, or an amino acid having an aromatic ring, or an N-methylated amino acid thereof; X7 is an amino acid containing an aromatic ring (e.g., W or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, an N-methylated amino acid, or an amino acid having a functional side chain; X9 is an amino acid containing an aromatic ring (e.g., W or a variant thereof); X10 is absent, or a polar amino acid (e.g., T or a variant thereof); X11 is absent, a hydrophilic amino acid, or an amino acid having a functional side chain; and X12 is C or a variant thereof.

[0212] In some embodiments, described herein is a peptide having formula (I) (e.g., a cyclic peptide) or a pharmaceutically acceptable salt thereof, wherein X1 is an amino acid (e.g., a D-amino acid); X2 is an amino acid containing an aromatic ring, or an N-methylated amino acid thereof; X3 is absent, a hydrophilic amino acid (e.g., N, Q, Cit, K or a variant thereof), G, Aib, Hgn, or Ala or a variant thereof (e.g., da); X4 is a hydrophobic amino acid, or a hydrophilic amino acid (e.g., Cit or a variant thereof); X5 is a hydrophilic amino acid (e.g., Dab, Dap, R, E or a variant thereof); X6 is absent, a hydrophilic amino acid, an amino acid having an aromatic ring (e.g., W), or an N-methylated amino acid thereof; X7 is an amino acid containing an aromatic ring (e.g., W or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, or an N-methylated amino acid; X9 is an amino acid containing an aromatic ring (e.g., W or a variant thereof); X10 is absent, or a hydrophilic amino acid (e.g., T or a variant thereof); X11 is absent, or a hydrophilic amino acid; and X12 is C or a variant thereof.

[0213] In some embodiments, described herein is a peptide having formula (I) (e.g., a cyclic peptide) or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is any amino acid, X2 is an amino acid having an aromatic ring or a variant thereof, X3 is N, X4 is a hydrophobic amino acid or a variant thereof; X5 is a hydrophilic amino acid or a variant thereof; X6 is a hydrophilic amino acid or an amino acid having an aromatic ring; X7 is W or a variant thereof; X8 is V or a hydrophilic amino acid or a variant thereof, X9 is W or a variant thereof; X10 is T or a variant thereof; X11 is a hydrophilic amino acid; X12 is C or a variant thereof (e.g., C).

[0214] In some embodiments, a peptide (e.g., a cyclic peptide) having formula (Ia) or a pharmaceutically acceptable salt thereof is described herein, X1-X2-X3-X4-X5-X6-X7-X8-X9-X12 Formula (Ia) wherein, X1 is any amino acid; X2 is an amino acid having an aromatic ring or a variant thereof; X3 is N or a variant thereof; X4 is a hydrophobic amino acid or a variant thereof, X5 is a hydrophilic amino acid or a variant thereof; X6 is a hydrophilic amino acid or an amino acid having an aromatic ring; X7 is W or a variant thereof; X8 is a hydrophilic amino acid or a variant thereof, X9 is W or a variant thereof; and X12 is C or a variant thereof.

[0215] In some embodiments, a (cyclic) peptide is described herein that has an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide consists of: the sequence of formula (I), X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) or a pharmaceutically acceptable salt thereof, wherein each of X1, X2, X3, X4, X5, X6, and X8 is independently an amino acid; X7 is W1Me or a variant thereof; X9 is W1Me or a variant thereof; Each of X10 and X11 is independently absent or is an amino acid; and X12 is cysteine (C) or a variant thereof.

[0216] In some embodiments, a peptide of formula (I) or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is any amino acid; X2 is an amino acid containing an aromatic ring or a variant thereof, or an N-methylated amino acid thereof; X3 is absent, N or a variant thereof; X4 is any hydrophobic amino acid or a variant thereof; X5 is a hydrophilic amino acid or a variant thereof; X6 is absent, a hydrophilic amino acid or an amino acid having an aromatic ring, or an N-methylated amino acid thereof; X7 is W or a variant thereof; X8 is V, a hydrophilic amino acid or a variant thereof, or an N-methylated amino acid; X9 is W or a variant thereof; X10 is absent, T or a variant thereof; X11 is absent, any hydrophilic amino acid; and X12 is C or a variant thereof.

[0217] In one aspect, described herein is a peptide or conjugate with a linker added thereto, comprising: (a) a (cyclic) peptide having an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide has the amino acid sequence of formula (I), X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is any D- or L-amino acid; X2 has the structure of, wherein ring A2 is phenyl or a 6-membered heteroaryl (e.g., heteroaryl having 1 or 2 Ns); R X2 are each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b, -OC(=O)NR c R d , -SH, SF5, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b , -NR c C(=O)NR d R b , -NR a , -NR b , -NR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally and independently substituted by one or more R XA substituted; kx2 is 0, 1, 2 or 3; mx2 is 0, 1, 2, 3 or 4; R NX2 is H, C1-C6 alkyl or C1-C6 haloalkyl; *X1 represents the attachment point to X1; and, *X3 represents the attachment point to X3; X3 has the structure of, wherein kx3 is 0, 1, 2 or 3; R NX3 is H, C1-C6 alkyl or C1-C6 haloalkyl; R X3 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; *X2 represents the attachment point to X2; and, *X4 represents the attachment point to X4; X4 is a hydrophobic amino acid (e.g., an amino acid having 4 or more carbon atoms in a side chain containing a straight-chain, branched-chain, or cyclic carbon chain), and wherein X4 is optionally N-alkylated by a C 1-3 alkyl group; X5 is a hydrophilic L-amino acid, such as an amino acid having the structure, wherein: R NX5 is H, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is optionally and independently substituted by one or more R XA substituents; R X5 is -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, SF5, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=NR b )NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is optionally and independently substituted by one or more R XA substituents; provided that R NX5 and R X5At least one of them contains a moiety selected from the following: -OH, -NH2, and -NH- (e.g., -NH-C(=NH)-NH2, -CO-NH2, -NH2, -COOH, -C(OH)-C 0-6 alkyl, -NH-CO-C 1-6 alkyl); *X4 represents the attachment point to X4; and, *X6 represents the attachment point to X6; X6 is (e.g., N, F), where R NX6 is H, C1-C6 alkyl, or C1-C6 haloalkyl; R X6 is -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, SF5, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=NR b )NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally and independently substituted by one or more R XA substituted; *X5 represents the attachment point to X5; and, *X7 represents the attachment point to X7; X7 has the structure of, where R NX7 is H, C1-C6 alkyl or C1-C6 haloalkyl; ring A7 is aryl or heteroaryl; R X7 each independently is halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, SF5, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2-halogen, -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; where the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally and independently substituted by one or more R XA substituted; kx7 is 0, 1, 2 or 3; mx7 is 0, 1, 2, 3, 4 or 5; *X6 represents the attachment point to X6; and, *X8 represents the attachment point to X8; X8 is an L-amino acid with -H attached to the α-amino group; X9 has The structure, wherein R NX9 is H, C1-C6 alkyl or C1-C6 haloalkyl; Ring A9 is aryl or heteroaryl; R X9 are each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, SF5, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally and independently substituted by one or more R XA substituents; kx9 is 0, 1, 2 or 3; mx9 is 0, 1, 2, 3, 4 or 5; *X8 represents the point of attachment to X8; and, *XC represents the point of attachment to (i) X10 or (i) X12 when both X10 and X11 are absent; X10 is absent or is an L-amino acid; X11 is absent or is an L-amino acid; provided that when X10 is absent, then X11 is also absent; and X12 is an L-amino acid having a reactive thiol group, such as Cys and Cys variants; Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heteroalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heteroalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Each R c and R d are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heteroalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Or R c and R d together with the atoms to which they are attached form a heteroalkyl optionally substituted with one or more R; and Each R and R XA are independently halogen, -CN, -OH, -OC1-C6 alkyl, SF5, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NR b C(=NR b )NR c R d, -NHC(=O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; and, (b) Optionally, a linker that links the peptide to a payload molecule.

[0218] In some embodiments, ring A7 is a 6-membered aryl or heteroaryl. In some embodiments, ring A7 is a 9- or 10-membered bicyclic aryl or heteroaryl. In some embodiments, the 6-, 9- or 10-membered heteroaryl has one heteroatom selected from N, O and S. In some embodiments, R NX7 is H. In some embodiments, each R X7 is independently selected from -CH3, -ethyl, -Cl and -F, and mx7 is 0, 1 or 2.

[0219] In some embodiments, X7 is W1Me, Nal1, Nal2, W1Et, Nal21N, 3Bzf, 3Bzt, Nal15N, Nal14N, Nal24N, Nal28N, F23dMe, F23dC, W1Me7N, or W1Me7Cl. In some embodiments, X7 is W1Me, F23dMe or W1Me7Cl.

[0220] In some embodiments, X9 is where each R X9 is independently selected from -OH, CN, NH2, C1-C3 alkyl, -Cl, -F, -Br, -CONH2 and -SO2F.

[0221] In some embodiments,

[0222] In some embodiments, each of R X9 is independently a halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)R a, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl.

[0223] In some embodiments, X9 is W1Me, W, Nal1, W1Et, Nal21N, 3Bzf, 3Bzt, Nal14N, Nal18N, F23dMe, F23dC or W1Et. In some embodiments, X9 is W1Me or F23dMe.

[0224] In some embodiments, ring A2 is a 6-membered heteroaryl containing 1 or 2 N atoms.

[0225] In some embodiments, R X5 is C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -C 0-6 alkylene-NH-C(=NH)-NH2, -C 0-6 alkylene-CO-NH2, -C 0-6 alkylene-COOH or -NH-CO-C 1-6 alkyl.

[0226] In some embodiments, X7 is W1Me, W1MeCl, W1MeBr, Nal1, Nal2, W1Et, 3Bzf, 3Bzt, F23dC, W1Me7N or F23dMe; X8 is V, KCOpipzaa, Hse, N, Cit, hCit, KAc, DapAc, OrnAc, T, alT, Aib, Alb, Q-reduced glucosamine, Hgl, E, Hgn, MeF, 3Py6NH2, W1Me, A, Q or K; and X9 is W1Me, Nal1, W1Et, Nal21N, 3Bzf, 3Bzt, Nal18N, F23dMe or F23dC.

[0227] In some embodiments, X7 is W1Me; X8 is V; and X9 is W1Me.

[0228] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (III-1) and (III-2), X1 is any amino acid (e.g., D-amino acid). In some embodiments, X1 is any of the standard amino acids. In some embodiments, X1 is a non-natural amino acid. In some embodiments, X1 is alanine (A). In some embodiments, X1 is D-alanine. In some embodiments, X1 is df3CON. In some embodiments, X1 is dkCOpipzaa. In some embodiments, X1 is dahp. In some embodiments, X1 is F. In some embodiments, X1 is an amino acid selected from Tables 5A to 5F. In some embodiments, the payload molecule or linker is attached to X1

[0229] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (III-1) and (III-2), X1 is any amino acid. In some embodiments, X1 is an amino acid (e.g., D-amino acid). In some embodiments, X1 is da, df3CON, dkCOpipzaa, dahp, dDab-NH2-Ph3-SO2F, dDap-NH2-Ph3-SO2F, dDap-NH2-Ph4-SO2F, dCit, Aib, G, norvaline, norleucine or dhAla. X1 is da. X1 is df3CON. X1 is dkCOpipzaa. X1 is dahp. X1 is dDab-NH2-Ph3-SO2F. X1 is dDap-NH2-Ph3-SO2F. X1 is dCit. X1 is Aib. X1 is G. X1 is norvaline. X1 is norleucine. X1 is dhAla. In some embodiments, X1 is F.

[0230] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (III-1) and (III-2), X2 is a standard amino acid. In some embodiments, X2 is a non-natural amino acid. In some embodiments, X2 is an aromatic amino acid or a variant thereof. In some embodiments, X2 is V. In some embodiments, X2 is an N-methylated amino acid or a variant thereof. In some embodiments, X2 is an N-alkylated amino acid or a variant thereof. In some embodiments, X2 is an amino acid containing an aryl group. In some embodiments, X2 is an amino acid containing an optionally substituted phenyl group. In some embodiments, X2 is an amino acid containing an optionally substituted naphthyl group. In some embodiments, X2 is an amino acid containing a heteroaryl group. In some embodiments, X2 is an amino acid containing an optionally substituted monocyclic heteroaryl group. In some embodiments, X2 is an amino acid containing an optionally substituted bicyclic heteroaryl group. In some embodiments, the aryl or heteroaryl is optionally substituted independently with 1, 2 or 3 substituents selected from: -CH3, -ethyl, -Cl and -F. In some embodiments, the aryl or heteroaryl is optionally substituted independently with 1, 2 or 3 substituents selected from: -OH, oxo, halogen, CN, amino, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkyl. In some embodiments, X2 is F or a variant thereof, and the unsubstituted phenyl ring of the variant of F is substituted with: (i) a phenyl ring substituted independently with 1 or 2 substituents selected from: -OH, -CN, -C 1-3 alkyl, or (ii) a 6-membered heteroaryl ring optionally substituted independently with 1 or 2 substituents selected from: -OH, -CN, -C 1-3An alkyl group, wherein the F or its structural variant is optionally N-methylated. In some embodiments, X2 is Me3Py. In some embodiments, X2 is In some embodiments, X2 is MeF. In some embodiments, X2 is MeF3H. In some embodiments, X2 is MeF3CN. In some embodiments, X2 is MeF3H. In some embodiments, X2 is Me4Py2NH2. In some embodiments, X2 is 4Py2NH2. In some embodiments, X2 is 4Py. In some embodiments, X2 is Me3Py. In some embodiments, X2 is an amino acid substituted with an aryl or heteroaryl group. In some embodiments, X2 is histidine (H). In some embodiments, X2 is phenylalanine, tryptophan, tyrosine, or a variant thereof. In some embodiments, X2 is phenylalanine or a variant thereof. In some embodiments, X2 is tryptophan or a variant thereof. In some embodiments, X2 is W1Me. In some embodiments, X2 is tyrosine or a variant thereof. In some embodiments, X2 is absent. In some embodiments, the payload molecule or linker is attached to X2. In some embodiments of formulae (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (Ia), (Ib), (Ic) and (III-2), X2 is an amino acid containing an aromatic ring, or its N-methylated amino acid. In some embodiments, X2 is an N-methylated amino acid. In some embodiments, X2 is an amino acid containing an aromatic ring. In some embodiments, X2 is an N-methylated amino acid containing an aromatic ring. In some embodiments, X2 is F or a variant thereof, Y or a variant thereof, or W or a variant thereof, or its N-methylated amino acid. In some embodiments, X2 is F or a variant thereof. In some embodiments, X2 is N-methyl F or a variant thereof. In some embodiments, X2 is Y or a variant thereof. In some embodiments, X2 is N-methyl Y or a variant thereof. In some embodiments, X2 is W or a variant thereof. In some embodiments, X2 is N-methyl W or a variant thereof. In some embodiments, X2 is MeF, Me3Py, MeF3CON, MeF3F, Me4Py or MeY(Me). In some embodiments, X2 is MeF. In some embodiments, X2 is Me3Py. In some embodiments, X2 is MeF3CON. In some embodiments, X2 is MeF3F. In some embodiments, X2 is Me4Py. In some embodiments, X2 is MeY. In some embodiments, X2 is MeY(Me).

[0231] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (III-1), and (III-2), X3 is a standard amino acid. In some embodiments, X3 is a non-natural amino acid. In some embodiments, X3 is asparagine (N). In some embodiments, X3 is a substitute of asparagine. In some embodiments, X3 is absent. In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (Ia), and (III-2), X3 is absent. In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (Ia), and (III-2), X3 is a hydrophilic amino acid (e.g., N, Hgn, Q, Cit, K, or a variant thereof), glycine (G), alanine (A), or a variant thereof (e.g., da, 2-aminoisobutyric acid (Aib)). In some embodiments, X3 is a hydrophilic amino acid. In some embodiments, X3 is an amino acid containing an -OH, -NH2, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3 group. In some embodiments, X3 has a charged side chain. In some embodiments, X3 has a positively charged side chain. In some embodiments, X3 has a negatively charged side chain. In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (Ia), and (III-2), X3 is an amino acid containing a charged side chain (e.g., K or a variant thereof), an amino acid containing a polar uncharged side chain (e.g., Q, Cit, N, or a variant thereof), or G, A, or a variant thereof. In some embodiments, X3 is an amino acid containing a charged side chain. In some embodiments, X3 is an amino acid containing a polar uncharged side chain. In some embodiments, X3 has a zwitterionic (e.g., KCOpipzaa) side chain. In some embodiments, X3 is zwitterionic. In some embodiments, X3 contains an -OH, -COOH, -NH-, or NH2 moiety. In some embodiments, X3 contains -OH, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3. In some embodiments, X3 contains the following side chains: C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -C 0-6 alkylene-NH-C(=NH)-NH2, -C 0-6 alkylene-CO-NH2, -C 0-6 alkylene-COOH or -NH-CO-C 1-6Alkyl. In some embodiments, X3 is absent, a hydrophilic amino acid (such as N, Q, Hgn, Cit, K or a variant thereof), G, Ala, or a variant thereof (e.g., da, ib). In some embodiments, X3 is N, Q, K, G, S, T, E, Aib, Hcit, Cit, Hgn, KCOpipzaa, Har, Nmm, Ndm, Ala, Hgl, 3Py6NH2, or a variant thereof, including D-amino acids (such as da) and variants (such as Q-reduced glucosamine). In some embodiments, X3 is absent, N, Q, Cit or a variant thereof, G, Aib, Hgn, K or a variant thereof, or Ala or a variant thereof (e.g., da). In some embodiments, X3 is absent, N, Q, Cit, G, Aib, Hgn, hCit, norCit, LysAc, OrnAc, Ala or da. In some embodiments, X3 is N or a variant thereof. In some embodiments, X3 is N. In some embodiments, X3 is Q or a variant thereof. In some embodiments, X3 is Q. In some embodiments, X3 is Cit or a variant thereof. In some embodiments, X3 is Cit, hCit or norCit. In some embodiments, X3 is Cit. In some embodiments, X3 is hCit. In some embodiments, X3 is norCit. In some embodiments, X3 is K or a substitution thereof. In some embodiments, X3 is K, LysAc or OrnAc. In some embodiments, X3 is K. In some embodiments, X3 is LysAc. In some embodiments, X3 is OrnAc. In some embodiments, X3 is G or a variant thereof. In some embodiments, X3 is G. In some embodiments, X3 is Hgn. In some embodiments, X3 is Aib. In some embodiments, X3 is Ala or a variant thereof. In some embodiments, X3 is Ala or da. In some embodiments, X3 is Ala. In some embodiments, X3 is da. In some embodiments, X3 is absent. In some embodiments, the payload molecule or linker is attached to X3. In some embodiments, X1 is directly bonded to X3.

[0232] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (III-1) and (III-2), X4 is a hydrophobic amino acid or a variant thereof. In some embodiments, X4 is a non-natural amino acid. In some embodiments, X4 is a standard amino acid. In some embodiments, X4 is leucine. In some embodiments, X4 contains 4 or more carbon atoms in the side chain, and the side chain contains a straight-chain, branched-chain or cyclic carbon chain. In some embodiments, X4 contains 4 or more consecutive carbon atoms in the side chain. In some embodiments, X4 contains an ethylene, propylene or butylene group in the side chain. In some embodiments, X4 is Cbg. In some embodiments, X4 is absent. In some embodiments, X4 is selected from glycine (G), methionine (M), alanine (A), valine (V), leucine (L), isoleucine (I), proline (P), phenylalanine (F), cysteine (C), and their substituents. In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (III-1) and (III-2), X4 is an amino acid containing a hydrophobic side chain (e.g., L), an amino acid containing a polar uncharged side chain (e.g., Cit or a variant thereof). In some embodiments, X4 is an amino acid containing a hydrophobic side chain. In some embodiments, X4 is an amino acid containing a polar uncharged side chain. In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (III-1) and (III-2), X4 is absent, a hydrophobic amino acid or a hydrophilic amino acid (e.g., Cit or a variant thereof). In some embodiments, X4 is absent, G substituted by a straight-chain or branched-chain C 1-5 alkyl group, A substituted by a C 3-7 cycloalkyl group, or Cit or a variant thereof. In some embodiments, X4 is absent, L, Cbg, Chg, Cba, Cha, Ahx, Dahp, citrulline (Cit), I, V, norleucine or norvaline. In some embodiments, X4 is absent. In some embodiments, X4 is a hydrophobic amino acid. In some embodiments, X4 is Leu, Hcit, Cbg, Chg or Cba. In some embodiments, X4 is Leu, Cbg, Chg or Cba. In some embodiments, X4 is G substituted by a straight-chain or branched-chain C 1-5 alkyl group. In some embodiments, X4 is G substituted by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or isopentyl. In some embodiments, X4 is a C 3-7Cycloalkyl-substituted A. In some embodiments, X4 is A substituted with a cyclopropyl group. In some embodiments, X4 is A substituted with a cyclobutyl group. In some embodiments, X4 is A substituted with a cyclopentyl group. In some embodiments, X4 is A substituted with a cyclohexyl group. In some embodiments, X4 is A substituted with a cycloheptyl group. In some embodiments, X4 is L, Cbg, Chg, Cba, Cha, Ahx, Dahp, I, V, norleucine or norvaline. In some embodiments, X4 is L. In some embodiments, X4 is Cbg. In some embodiments, X4 is Chg. In some embodiments, X4 is Cba. In some embodiments, X4 is Cha. In some embodiments, X4 is Ahx. In some embodiments, X4 is Dahp. In some embodiments, X4 is I. In some embodiments, X4 is V. In some embodiments, X4 is norleucine. In some embodiments, X4 is norvaline. In some embodiments, X4 is a hydrophilic amino acid. In some embodiments, X4 is Cit or a variant thereof. In some embodiments, X4 is Cit. In some embodiments, X4 is optionally N-methylated. In some embodiments, a payload molecule or linker is attached to X4. In some embodiments, X1 is directly bonded to X4. In some embodiments of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (III-1) and (III-2), X4 is a hydrophilic amino acid. In some embodiments, X4 is an amino acid containing an -OH, -NH2, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2 or -NHC(O)CH3 group. In some embodiments, X4 has a charged side chain. In some embodiments, X4 has a positively charged side chain. In some embodiments, X4 has a negatively charged side chain. In some embodiments, X4 is zwitterionic. In some embodiments, X4 contains an -OH, -COOH, -NH- or NH2 moiety. In some embodiments, X4 contains -OH, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2 or -NHC(O)CH3. In some embodiments, X4 contains the following side chains: C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -C 0-6 alkylene-NH-C(=NH)-NH2, -C 0-6 alkylene-CO-NH2, -C 0-6 alkylene-COOH or -NH-CO-C 1-6 alkyl.

[0233] In some embodiments of formulae (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (III-1) and (III-2), X4 is a hydrophobic amino acid. In some embodiments, X4 comprises at least 4 contiguous carbon atoms and may be straight-chain or branched. In some embodiments, X4 comprises at least 5 contiguous carbon atoms and may be straight-chain or branched. In some embodiments, X4 comprises a propylene moiety in the side chain. In some embodiments, X4 comprises a butylene moiety in the side chain.

[0234] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (III-1) and (III-2), X5 is a hydrophilic amino acid or a variant thereof. In some embodiments, X5 is a hydrophilic amino acid. In some embodiments, X5 is a non-natural amino acid. In some embodiments, X5 is a positively charged amino acid. In some embodiments, X5 is a negatively charged amino acid. In some embodiments, X5 is uncharged. In some embodiments, X5 is a standard amino acid. In some embodiments, X5 is Ala or a variant thereof. In some embodiments, X5 is N, Q, K, G, S, T, E, Aib, Hcit, Cit, Hgn, KCOpipzaa, Har, Nmm, Ndm, Ala, Hgl, 3Py6NH2, or a variant thereof, including D-amino acids (e.g., da) and variants (e.g., Q-reduced glucosamine). In some embodiments, X5 is Hgn, N, Q-reduced glucosamine, KCOpipzaa, Hgl, Nmm, Ndm, KCOpipzaa, K, S, T or E. In some embodiments, X5 is Hgn. In some embodiments, X5 is asparagine (N). In some embodiments, X5 is Q-reduced glucosamine. In some embodiments, X5 is Hgl. In some embodiments, X5 is Nmm. In some embodiments, X5 is Ndm. In some embodiments, X5 is KCOpipzaa. In some embodiments, X5 is Dab. In some embodiments, X5 is S. In some embodiments, X5 is K. In some embodiments, X5 is absent. In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (III-1) and (III-2), X5 is an amino acid containing a charged side chain (e.g., E, Hgl, D, or a variant thereof) or an amino acid containing a polar uncharged side chain (e.g., Q, Cit, Hgn, N, or a variant thereof). In some embodiments, X5 is an amino acid containing a charged side chain. In some embodiments, X5 is an amino acid containing a polar uncharged side chain. In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (Ia), (Ib) and (III-2), X5 is absent, a hydrophilic amino acid or a variant thereof. In some embodiments, X5 is absent, a hydrophilic amino acid or an amino acid having a functional side chain (e.g., Dab, Dap, R, E), wherein the hydrophilic amino acid comprises an L-amino acid, and the L-amino acid comprises -NH2, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2 or -NHC(O)CH3.In some embodiments, X5 is absent, Hgl, Hgn, Dab, Dap, DabAc, DapAc, R, hArg, E or D. In some embodiments, X5 is absent. In some embodiments, X5 is a hydrophilic amino acid. In some embodiments, X5 is an amino acid containing -NH2, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2 or -NHC(O)CH3. In some embodiments, X5 is an L-amino acid containing -NH2, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2 or -NHC(O)CH3. In some embodiments, X5 is Hgl. In some embodiments, X5 is Hgn. In some embodiments, X5 is Dab. In some embodiments, X5 is Dap. In some embodiments, X5 is DabAc. In some embodiments, X5 is DapAc. In some embodiments, X5 is R or a variant thereof. In some embodiments, X5 is R or hArg. In some embodiments, X5 is R. In some embodiments, X5 is hArg. In some embodiments, X5 is E. In some embodiments, X5 is hCit. In some embodiments, X5 is G. In some embodiments, X5 is D. In some embodiments, a linker is attached to X5. In some embodiments, X1 is directly bonded to X5.

[0235] In some embodiments of formulae (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ic), (III-1) and (III-2), X6 is any amino acid. In some embodiments, X6 is a standard amino acid. In some embodiments, X6 is a non-natural amino acid. In some embodiments, X6 is a hydrophilic amino acid or an amino acid having an aromatic ring, or an N-methylated amino acid thereof, or a substituent thereof. In some embodiments, X6 is an amino acid having an aromatic ring or a substituent thereof. In some embodiments, X6 is an amino acid containing an aryl group. In some embodiments, X6 is an amino acid containing an optionally substituted phenyl group. In some embodiments, X6 is an amino acid containing an optionally substituted naphthyl group. In some embodiments, X6 is an amino acid containing a heteroaryl group. In some embodiments, X6 is an amino acid containing an optionally substituted monocyclic heteroaryl group. In some embodiments, X6 is an amino acid containing an optionally substituted bicyclic heteroaryl group. In some embodiments, the aryl or heteroaryl is optionally substituted independently with 1, 2 or 3 substituents selected from: -CH3, -ethyl, -Cl and -F. In some embodiments, the aryl or heteroaryl is optionally substituted independently with 1, 2 or 3 substituents selected from: -OH, oxo, halogen, CN, amino, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkyl. In some embodiments, X6 is an N-methylated amino acid. In some embodiments, X6 is a hydrophilic amino acid or a substituent thereof. In some embodiments, X6 is an amino acid having an aromatic ring or a substituent thereof. In some embodiments, X6 is an N-methylated amino acid or a substituent thereof. In some embodiments, X6 is MeE. In some embodiments, X6 is N. In some embodiments, X6 is MeN. In some embodiments, X6 is Me3Py. In some embodiments, X6 is MeF. In some embodiments, X6 is Q-reduced glucosamine. In some embodiments, X6 is MeF4C. In some embodiments, X6 is absent. In some embodiments of formulae (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ic), (III-1) and (III-2), X6 is an amino acid containing a charged side chain (e.g., E, Hgl, D, or a variant thereof) or an amino acid containing a polar uncharged side chain (e.g., Q, Cit, Hgn, N, or a variant). In some embodiments, X6 is an amino acid containing a charged side chain. In some embodiments, X6 is an amino acid containing a polar uncharged side chain. In some embodiments of formulae (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (Ia), (Ic) and (III-2), X6 is absent, a hydrophilic amino acid, an amino acid containing an aromatic ring, or an N-methylated amino acid thereof.In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (III-1) and (III-2), X6 is a hydrophilic amino acid. In some embodiments, X6 is an amino acid comprising an -OH, -NH2, -C(O)OH, -NHC(═NH)NH2, -NHC(O)NH2, -C(O)NH2 or -NHC(O)CH3 group. In some embodiments, X6 has a charged side chain. In some embodiments, X6 has a positively charged side chain. In some embodiments, X6 has a negatively charged side chain. In some embodiments, X6 is zwitterionic. In some embodiments, X6 comprises an -OH, -COOH, -NH- or NH2 moiety. In some embodiments, X6 comprises -OH, -C(O)OH, -NHC(═NH)NH2, -NHC(O)NH2, -C(O)NH2 or -NHC(O)CH3. In some embodiments, X6 comprises the following side chains: C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -C. 0-6 alkylene-NH-C(═NH)-NH2, -C 0-6 alkylene-CO-NH2, -C 0-6 alkylene-COOH or -NH-CO-C 1-6Alkyl. In some embodiments, X6 is absent, a hydrophilic amino acid, F or its variant, Y or its variant, W or its variant, or its N-methylated amino acid, wherein the hydrophilic amino acid comprises a substituent selected from the group consisting of -C(O)OH, -C(O)NH2, and -NHC(O)CH3. In some embodiments, X6 is absent, MeF, MeE, Me3Py, Me4Py, MeF4F, MeF4C, or MeY. In some embodiments, X6 is MeE, MeN, Me3Py, MeF, MeF4C, or N. In some embodiments, X6 is absent. In some embodiments, X6 is a hydrophilic amino acid. In some embodiments, X6 is an amino acid comprising -NH2, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3. In some embodiments, X6 is E or its N-methylated amino acid. In some embodiments, X6 is E. In some embodiments, X6 is MeE. In some embodiments, X6 is an amino acid comprising an aromatic ring, or its N-methylated amino acid. In some embodiments, X6 is an amino acid comprising an optionally substituted phenyl group. In some embodiments, X6 is an amino acid comprising an optionally substituted heteroaryl group. In some embodiments, X6 is F or its variant, or its N-methylated amino acid. In some embodiments, X6 is F, MeF, Me3Py, Me4Py, MeF4F, or MeF4C. In some embodiments, X6 is F. In some embodiments, X6 is MeF. In some embodiments, X6 is Me3Py. In some embodiments, X6 is Me4Py. In some embodiments, X6 is MeF4F. In some embodiments, X6 is MeF4C. In some embodiments, X6 is Y or its variant, or its N-methylated amino acid. In some embodiments, X6 is Y or MeY. In some embodiments, X6 is Y. In some embodiments, X6 is MeY. In some embodiments, the payload molecule or linker is attached to X6. In some embodiments, X1 is directly bonded to X6.

[0236] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (III-1) and (III-2), X7 is W or a variant thereof. In some embodiments, X7 is a standard amino acid. In some embodiments, X7 is a non-natural amino acid. In some embodiments, X7 is W1Me. In some embodiments, X7 is W1Me7Cl. In some embodiments, X7 is W1Me7N. In some embodiments, X7 is absent. In some embodiments, X7 is an amino acid having an aromatic ring or a substituent thereof. In some embodiments, X7 is an amino acid containing an aryl group. In some embodiments, X7 is an amino acid containing an optionally substituted phenyl group. In some embodiments, X7 is an amino acid containing an optionally substituted naphthyl group. In some embodiments, X7 is an amino acid containing a heteroaryl group. In some embodiments, X7 is an amino acid containing an optionally substituted monocyclic heteroaryl group. In some embodiments, X7 is an amino acid containing an optionally substituted bicyclic heteroaryl group. In some embodiments, the aryl or heteroaryl is optionally substituted independently with 1, 2 or 3 substituents selected from: -CH3, -ethyl, -Cl and -F. In some embodiments, the aryl or heteroaryl is optionally substituted independently with 1, 2 or 3 substituents selected from: -OH, oxo, halogen, CN, amino, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkyl. In some embodiments, X7 is W, Y or a variant thereof (e.g., an amino acid having a 6-membered aryl or heteroaryl, or a 9- or 10-membered bicyclic aryl or heteroaryl linked to the α-carbon through carbon (e.g., a methylene group), wherein the 6-, 9- and 10-membered heteroaryls have one heteroatom (e.g., N), and wherein the 6-, 9- and 10-membered aryl or heteroaryl is optionally substituted independently with 1 or 2 substituents selected from: –CH3, -ethyl, -Cl and -F). In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (III-1) and (III-2), X7 is an amino acid containing an aromatic ring. In some embodiments, X7 is an amino acid containing an aromatic ring (e.g., W or a variant thereof). In some embodiments, X7 is F or a variant thereof, or W or a variant thereof. In some embodiments, X7 is W1Me, W1Me7Cl, W1Me7N, W, F, 7-AzaTrp, W7Me or W1Et. In some embodiments, X7 is F or a variant thereof. In some embodiments, X7 is F. In some embodiments, X7 is W or a variant thereof.In some embodiments, X7 is Nal1, Nal2, W1Et, Nal21N, 3Bzf, 3Bzt, Nal15N, Nal14N, Nal24N, Nal28N, F23dC, W1Me, W1Me7Cl or W1Me7N. In some embodiments, X7 is W1Me, W1Me7Cl, W1Me7N, W, 7-AzaTrp, W7Me or W1Et. In some embodiments, X7 is W1Me, W1Me7Cl or F23dMe. In some embodiments, X7 is W1Me, W1Me7Cl, Nal1, Nal2, W1Et, Nal21N, 3Bzf, 3Bzt, Nal15N, Nal14N, Nal24N, Nal28N, F23dC or W1Me7N. In some embodiments, X7 is W1Me, W1Me7Cl or W1Me7N. In some embodiments, X7 is W1Me. In some embodiments, X7 is W1Me7Cl. In some embodiments, X7 is W1Me7N. In some embodiments, X7 is W. In some embodiments, X7 is 7-AzaTrp. In some embodiments, X7 is W7Me. In some embodiments, the payload molecule or linker is attached to X7. In some embodiments, X1 is directly bonded to X7.

[0237] In some embodiments of formulae (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (III-1) and (III-2), X8 is any amino acid. In some embodiments, X8 is any of the standard amino acids. In some embodiments, X8 is a non-natural amino acid. In some embodiments, X8 is V, a hydrophilic amino acid, an N-methylated amino acid, or a substituent thereof. In some embodiments, X8 is V. In some embodiments, X8 is phenylalanine, tryptophan, tyrosine, or a variant thereof. In some embodiments, X8 is phenylalanine or a variant thereof. In some embodiments, X8 is tryptophan or a variant thereof. In some embodiments, X8 is W1Me. In some embodiments, X8 is tyrosine or a variant thereof. In some embodiments, X8 is an N-methylated amino acid or a substituent thereof. In some embodiments, X8 is an N-alkylated amino acid or a substituent thereof. In some embodiments, X8 is KCOpipzaa. In some embodiments, X8 is K. In some embodiments, X8 is valine (V). In some embodiments, X8 is Q-reduced glucosamine. In some embodiments, X8 is Cit. In some embodiments, X8 is hCit. In some embodiments, X8 is absent. In some embodiments of formulae (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (III-1) and (III-2), X8 is a hydrophobic amino acid, a hydrophilic amino acid, an N-methylated amino acid or an amino acid having a functional side chain. In some embodiments; X8 is G substituted with one or two straight-chain or branched C 1-5 alkyl, C 3-7A cycloalkyl-substituted A, or a hydrophilic amino acid, where the hydrophilic amino acid includes L-amino acids containing the following: -NH2, one or more -OH, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2, -NHC(O)CH3; or the hydrophilic amino acid contains zwitterions. In some embodiments, X8 is V, A, E, N, K, Q-reduced glucosamine, KCOpipzaa, Q, Hse, N, Cit, Hcit, Kac, DapAc, OrnAc, T, alT, Aib, Alb or 3Py6NH2. In some embodiments, X8 is A, E, N, K, Q-reduced glucosamine, KCOpipzaa, Q, Hse, N, Cit, Hcit, Kac, DapAc, OrnAc, T, alT, Aib, Alb or 3Py6NH2. In some embodiments, X8 is KCOpipzaa, N, Cit, Q-reduced glucosamine, hCit, K, KAc, Aib, Alb, DapAc, OrnAc, A, T, alT, norleucine, norvaline, Hgl, E, Hgn, Q, I or L. In certain embodiments, X8 is KCOpipzaa, V, Q-reduced glucosamine, Cit, Hcit, K or 3Py6NH2. In certain embodiments, X8 is KCOpipzaa, Q-reduced glucosamine, Cit, Hcit, K or 3Py6NH2. In some embodiments, X8 is V, KCOpipzaa, Cit, Q-reduced glucosamine, hCit, Aib, Alb, norleucine or norvaline. In some embodiments, X8 is KCOpipzaa, Cit, Q-reduced glucosamine, hCit, Aib, Alb, norleucine or norvaline. In some embodiments, X8 is KCOpipzaa, N, Cit, hCit, KAc, DapAc, OrnAc, A, T, alT, Aib, Alb, Q-reduced glucosamine, Hgl, Q, E, Hgn or K. In some embodiments, X8 is a hydrophobic amino acid. In some embodiments, X8 is G substituted with a straight-chain or branched C 1-5 alkyl-substituted G. In some embodiments, X8 is G substituted with one or more substituents selected from the following: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and isopentyl. In some embodiments, X8 is C 3-7Cycloalkyl-substituted A. In some embodiments, X8 is A substituted with cyclopropyl. In some embodiments, X8 is A substituted with cyclobutyl. In some embodiments, X8 is A substituted with cyclopentyl. In some embodiments, X8 is A substituted with cyclohexyl. In some embodiments, X8 is A substituted with cycloheptyl. In some embodiments, X8 is V, Aib, Alb, norleucine, or norvaline. In some embodiments, X8 is Aib, Alb, norleucine, or norvaline. In some embodiments, X8 is V. In some embodiments, X8 is Aib. In some embodiments, X8 is Alb. In some embodiments, X8 is norleucine. In some embodiments, X8 is norvaline. In some embodiments, X8 is a hydrophilic amino acid. In some embodiments, X8 is an amino acid containing -NH2, one or more -OH, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3. In some embodiments, X8 is an L-amino acid containing -NH2, one or more -OH, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3. In some embodiments, X8 is an amino acid containing zwitterion. In some embodiments, X8 is Cit or a variant thereof. In some embodiments, X8 is Cit or hCit. In some embodiments, X8 is KCOpipzaa. In some embodiments, X8 is Q-reduced glucosamine. In some embodiments, a payload molecule or linker is attached to X8. In some embodiments, X1 is directly bonded to X8.

[0238] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (III-1) and (III-2), X9 is W or a variant thereof. In some embodiments, X9 is a standard amino acid. In some embodiments, X9 is a non-natural amino acid. In some embodiments, X9 is W1Me, W1Me7Cl, F23dMe, Nal1, Nal2, W1Et, Nal21N, 3Bzf, 3Bzt, Nal15N, Nal14N, Nal24N, Nal28N, F23dC, or W1Me7N. In some embodiments, X9 is W1Me or F23dMe. In some embodiments, X9 is W1Me. In some embodiments, X9 is W1Me7Cl. In some embodiments, X9 is W1Me7N. In some embodiments, X9 is absent. In some embodiments, X9 is F23dMe. In some embodiments, X9 is an amino acid having an aromatic ring or a substituent thereof. In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (III-1) and (III-2), X9 is an amino acid containing an aromatic ring. In some embodiments, X9 is an amino acid containing an aryl group. In some embodiments, X9 is an amino acid containing an optionally substituted phenyl group. In some embodiments, X9 is an amino acid containing an optionally substituted naphthyl group. In some embodiments, X9 is an amino acid containing a heteroaryl group. In some embodiments, X9 is an amino acid containing an optionally substituted monocyclic heteroaryl group. In some embodiments, X9 is an amino acid containing an optionally substituted bicyclic heteroaryl group. In some embodiments, the aryl or heteroaryl is optionally substituted independently with 1, 2 or 3 substituents selected from: -CH3, -ethyl, -Cl and -F. In some embodiments, the aryl or heteroaryl is optionally substituted independently with 1, 2 or 3 substituents selected from: -OH, oxo, halogen, CN, amino, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkyl. In some embodiments, X9 is W, Y or a variant thereof (e.g., an amino acid having a 6-membered aryl or heteroaryl, or a 9- or 10-membered bicyclic aryl or heteroaryl connected to the α-carbon through carbon (e.g., a methylene group), wherein the 6-, 9- and 10-membered heteroaryl has one heteroatom (e.g., N), and wherein the 6-, 9- and 10-membered aryl or heteroaryl is optionally substituted independently with 1 or 2 substituents selected from: –CH3, -ethyl, -Cl and -F). In some embodiments, X9 is an amino acid containing an aromatic ring (e.g., W or a variant thereof). In some embodiments, X9 is F or a variant thereof, or W or a variant thereof.In some embodiments, X9 is W1Me, W1Me7Cl, W1Me7N, F23dMe, W1Et, W7Me, W, F, or 7-AzaTrp. In some embodiments, X9 is F or a variant thereof. In some embodiments, X9 is F or F23dMe. In some embodiments, X9 is F. In some embodiments, X9 is F23dMe. In some embodiments, X9 is W or a variant thereof. In some embodiments, X9 is W1Me, W1Me7Cl, W1Me7N, W, 7-AzaTrp, W7Me or W1Et. In some embodiments, X9 is W1Me or F23dMe. In some embodiments, X9 is W1Me. In some embodiments, X9 is W1Me7Cl. In some embodiments, X9 is W1Me7N. In some embodiments, X9 is W. In some embodiments, X9 is 7-AzaTrp. In some embodiments, X9 is W7Me. In some embodiments, X9 is W1Et. In some embodiments, a payload molecule or linker is attached to X9. In some embodiments, X1 is directly bonded to X9.

[0239] In some embodiments of formulae (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1) and (III-2), X10 is absent, T or a variant thereof. In some embodiments, X10 is a standard amino acid. In some embodiments, X10 is a non-natural amino acid. In some embodiments, X10 is threonine (T). In some embodiments, X10 is absent. In some embodiments of formulae (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1) and (III-2), X10 is absent, or a polar amino acid (e.g., T or a variant thereof). In some embodiments, X10 is absent, Q, Hgn, S or a variant thereof, optionally substituted with a straight or branched C 1-5An alkyl-substituted T or a variant thereof, K or a variant thereof, Cit or a variant thereof, or an L-amino acid substituted with -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3. In some embodiments, X10 is absent, T, Q, S, Hgn, α-methylserine, hSer, hThr, N, OrnAc, LysAc, Cit, or hCit. In some embodiments, X10 is absent. In some embodiments, X10 is a polar amino acid. In some embodiments, X10 is Q. In some embodiments, X10 is Hgn. In some embodiments, X10 is S or a variant thereof. In some embodiments, X10 is S, α-methylserine, or hSer. In some embodiments, X10 is S. In some embodiments, X10 is α-methylserine. In some embodiments, X10 is hSer. In some embodiments, X10 is optionally a straight-chain or branched C 1-5 An alkyl-substituted T or a variant thereof. In some embodiments, X10 is T or hThr. In some embodiments, X10 is T. In some embodiments, X10 is hThr. In some embodiments, X10 is T substituted with methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, or isopentyl. In some embodiments, X10 is N. In some embodiments, X10 is K or a variant thereof. In some embodiments, X10 is K, OrnAc, or LysAc. In some embodiments, X10 is K. In some embodiments, X10 is OrnAc. In some embodiments, X10 is LysAc. In some embodiments, X10 is Cit or a variant thereof. In some embodiments, X10 is Cit or hCit. In some embodiments, X10 is Cit. In some embodiments, X10 is hCit. In some embodiments, a payload molecule or linker is attached to X10. In some embodiments, X1 is directly bonded to X10.

[0240] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1) and (III-2), X11 is absent, a hydrophilic amino acid, or a substituent thereof. In some embodiments, X11 is serine, threonine, tyrosine, asparagine, glutamine or a substituent thereof. In some embodiments, X11 is a standard amino acid. In some embodiments, X11 is a non-natural amino acid. In some embodiments, X11 is Hgn. In some embodiments, X11 is K. In some embodiments, X11 is glutamic acid. In some embodiments, X11 is hArg. In some embodiments, X11 is hCit. In some embodiments, X11 is Nmm. In some embodiments, X11 is Ndm. In some embodiments, X11 is Har. In some embodiments, X11 is R. In some embodiments, X11 is Har. In some embodiments, X11 is Arg (R). In some embodiments, X11 is Cit. In some embodiments, X11 is asparagine. In some embodiments, X11 is absent. In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1) and (III-2), X11 is absent, a hydrophilic amino acid or an amino acid having a functional side chain. In some embodiments, X11 is a hydrophilic amino acid. In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1) and (III-2), X11 is an amino acid comprising a charged side chain (e.g., E, Hgl, D, R, hArg, K or a variant thereof) or an amino acid comprising a polar uncharged side chain (e.g., Q, Cit, Hgn, N, or a variant thereof). In some embodiments, X11 is an amino acid comprising a charged side chain. In some embodiments, X11 is an amino acid comprising a polar uncharged side chain. In some embodiments, X11 is an amino acid comprising an -OH, -NH2, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2 or -NHC(O)CH3 group. In some embodiments, X11 has a charged side chain. In some embodiments, X11 has a positively charged side chain. In some embodiments, X11 has a negatively charged side chain. In some embodiments, X11 is zwitterionic. In some embodiments, X11 comprises an -OH, -COOH, -NH- or NH2 moiety. In some embodiments, X11 comprises -OH, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2 or -NHC(O)CH3. In some embodiments, X11 comprises the following side chains: C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -C 0-6Alkylene-NH-C(=NH)-NH2, -C 0-6 Alkylene-CO-NH2, -C 0-6 Alkylene-COOH or -NH-CO-C 1-6Alkyl. In some embodiments, X11 is absent, E, Hgn, R or its variant, Cit or its variant, Hgl, K or its variant, D, N or Q. In some embodiments, X11 is absent, E, Hgn, R, hArg, Cit, hCit, Hgl, Orn, D, N, Q, DapAc, OrnAc, DabAc or norCit. In some embodiments, X11 is absent, arginine (R), asparagine (N), aspartic acid (D), glutamine (Q), lysine (K) or a non-natural hydrophilic amino acid. In some embodiments, X11 is absent, Hgn, R, hArg, Cit, hCit, Hgl, Orn, D, N, Q, DapAc, OrnAc, DabAc or norCit. In some embodiments, X11 is Hgn, R, hArg, Cit, hCit, Hgl, Orn, D, N, Q, DapAc, OrnAc, DabAc or norCit. In some embodiments, X11 is Q, K, G, S, T, E, Aib, Hcit, Cit, Hgn, KCOpipzaa, Har, Nmm, Ndm, Ala, Hgl, 3Py6NH2, or its variant, including D-amino acids (such as da) and variants (such as Q-reduced glucosamine). In some embodiments, X11 is Q, K, G, S, T, Aib, Hcit, Cit, Hgn, KCOpipzaa, Har, Nmm, Ndm, Ala, Hgl, 3Py6NH2 or its variant, including D-amino acids (such as da) and variants (such as Q-reduced glucosamine). In some embodiments, X11 is Hgn, N, R, Har, Nmm, Ndm, E or K. In some embodiments, X11 is absent. In some embodiments, X11 is a hydrophilic amino acid. In some embodiments, X11 is E. In some embodiments, X11 is Hgn. In some embodiments, X11 is R or its variant. In some embodiments, X11 is R or hArg. In some embodiments, X11 is R. In some embodiments, X11 is hARg. In some embodiments, X11 is Cit or its variant. In some embodiments, X11 is Cit, hCit or norCit. In some embodiments, X11 is Cit. In some embodiments, X11 is hCit. In some embodiments, X11 is norCit. In some embodiments, X11 is Hgl. In some embodiments, X11 is K or its variant. In some embodiments, X11 is K, Orn, OrnAc, DabAc or DapAc. In some embodiments, X11 is K. In some embodiments, X11 is Orn. In some embodiments, X11 is OrnAc. In some embodiments, X11 is DabAc. In some embodiments, X11 is DapAc. In some embodiments, X11 is D, N or Q.In some embodiments, X11 is D. In some embodiments, X11 is N. In some embodiments, X11 is Q. In some embodiments, a payload molecule or linker is attached to X11. In some embodiments, X1 is directly bonded to X11.

[0241] In some embodiments of formulae (I), (I-5), (Ia), (Ib), (Ic) and (III-2), X12 is C or a variant thereof. In some embodiments, X12 is a standard amino acid. In some embodiments, X12 is a non-natural amino acid. In some embodiments, X12 is cysteine. In some embodiments, X12 is a substitute of cysteine. In some embodiments, X12 is homocysteine. In some embodiments, X12 is CdMe. In some embodiments, X12 is C3SMe. In some embodiments, X12 is C3RMe. In some embodiments, a payload molecule or linker is attached to X12. In some embodiments of formulae (I), (I-5), (Ia), (Ib), (Ic) and (III-2), X12 is C or a variant thereof. In some embodiments, X12 is C, hCys, CdMe, C3RMe, C3SMe, selenocysteine, dc or penicillamine. In some embodiments, X12 is C. In some embodiments, X12 is hCys. In some embodiments, X12 is CdMe. In some embodiments, X12 is C3RMe. In some embodiments, X12 is C3SMe. In some embodiments, X12 is selenocysteine. In some embodiments, X12 is dc. In some embodiments, X12 is penicillamine. In some embodiments, a payload molecule or linker is attached to X12. In some embodiments, X1 is directly bonded to X12.

[0242] In some embodiments, the peptide or a pharmaceutically acceptable salt thereof has a cyclic structure, wherein the first amino acid (or X1) is covalently linked to the last amino acid (or X12).

[0243] In some embodiments, the peptide or a pharmaceutically acceptable salt thereof has a cyclic structure having an amino acid (e.g., a chloroacetylated amino acid) at the first residue X1 and a cysteine residue or a variant thereof, and wherein the amino acid at X1 (e.g., the chloroacetylated amino acid) forms a covalent bond with the cysteine residue or a variant thereof.

[0244] In some embodiments, the peptide has a monocyclic structure. In certain embodiments, the amino acid X1 forms a covalent bond with cysteine or a variant thereof.

[0245] In some embodiments, the peptide having formula (I) has the structure of formula (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of: NH2 and OH; R 2 is selected from the group consisting of: H or C 1-3 alkyl; R 3 is selected from the group consisting of: H or C 1-3 alkyl; wherein the attachment point to the payload molecule or linker is not shown, and wherein X1-X11 are described in formula (I).

[0246] In some embodiments, the peptide having formula (I-1) has the structure of formula (I-2) or a pharmaceutically acceptable salt thereof,

[0247] In some embodiments, the peptide having formula (I-1) has the structure of formula (I-3) or a pharmaceutically acceptable salt thereof,

[0248] In some embodiments, the peptide having formula (I-1) has the structure of formula (I-4) or a pharmaceutically acceptable salt thereof,

[0249] In some embodiments of formula (I-1), (I-2), (I-3) or (I-4), R 1 is OH. In some embodiments of formula (I-1), (I-2), (I-3) or (I-4), R 1 is NH2.

[0250] In some embodiments of formula (I-1), (I-2), (I-3) or (I-4), R 2 is H. In some embodiments of formula (I-1), (I-2), (I-3) or (I-4), R 2 is C 1-3 alkyl. In some embodiments of formula (I-1), (I-2), (I-3) or (I-4), R 2 is methyl.

[0251] In some embodiments of formula (I-1), (I-2), (I-3) or (I-4), R 3 is H. In some embodiments of formula (I-1), (I-2), (I-3) or (I-4), R 3 is C 1-3 alkyl. In some embodiments of formula (I-1), (I-2), (I-3) or (I-4), R3 is methyl.

[0252] In some embodiments, the peptide having formula (I) has the structure of formula (I-5) or a pharmaceutically acceptable salt thereof, wherein X1-X12 have the above definitions, and Lcyc is a closed-loop group covalently connecting X1 and X12.

[0253] In some embodiments, Lcyc is a group selected from Table 4B. In some embodiments, Lcyc is formed by the reaction of the first and second functional groups in Table 4C.

[0254] In some embodiments, the peptide having formula (I) or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is any amino acid (e.g., D-amino acid); X2 is an amino acid containing an aromatic ring or a variant thereof, or an N-methylated amino acid thereof; X3 is N or a variant thereof; X4 is any hydrophobic amino acid or a variant thereof; X5 is a hydrophilic amino acid or a variant thereof; X6 is a hydrophilic amino acid or an amino acid having an aromatic ring, or an N-methylated amino acid thereof; X7 is W or a variant thereof; X8 is V or a hydrophilic amino acid or a variant thereof; X9 is W or a variant thereof; X10 is T or a variant thereof; X11 is any hydrophilic amino acid; and X12 is C or a variant thereof.

[0255] In some embodiments of formula (I), wherein, X1 is a D-amino acid (e.g., da, df3CON, dahp or dkCOpipzaa); X2 is N-methylated phenylalanine or a variant thereof (e.g., Me3Py, MeF, MeF3H or MeF3CN); X3 is N; X4 is a hydrophobic amino acid or an N-methylated amino acid (e.g., leucine, Cbg or Chg); X5 is Hgn, asparagine (N), 2,4-diaminobutyric acid (Dab), Q-reduced glucosamine, KCOpipzaa, Hgl, Nmm, Ndm or lysine (K); X6 is asparagine (N) or N-methylated glutamate (E), N-methylated asparagine, N-methylated phenylalanine (F) or its substitution (e.g., Q-reduced glucosamine, MeE, MeN, Me3Py, MeF, MeF4C or N); X7 is W1Me, W1Me7Cl or W1Me7N; X8 is KCOpipzaa, V, Q-reduced glucosamine, Cit, Hcit or K; X9 is W1Me or F23dMe; X10 is T; X11 is hArg, hCit, citrulline (Cit), A Hgn, asparagine (N), arginine (R), Har, Nmm, Ndm, glutamate (E), lysine (K); and X12 is cysteine.

[0256] In some embodiments, the amino acid of formula (I) has the sequence of formula (Ia) or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X12 Formula (Ia).

[0257] In some embodiments, the amino acid of formula (I) has the sequence of formula (Ib) or a pharmaceutically acceptable salt thereof, X1-X2-X4-X5-X7-X8-X9-X12 Formula (Ib).

[0258] In some embodiments, the amino acid of formula (I) has the sequence of formula (Ic) or a pharmaceutically acceptable salt thereof, X1-X2-X6-X7-X8-X9-X12 Formula (Ic).

[0259] In some embodiments, the peptide described herein has an amino acid sequence according to formula (Ia) or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X12 Formula (Ia) wherein, X1 is any amino acid (e.g., D-amino acid); X2 is an amino acid containing an aromatic ring or its variant, or its N-methylated amino acid; X3 is N or its variant; X4 is any hydrophobic amino acid or a variant thereof, X5 is a hydrophilic amino acid or a variant thereof; X6 is a hydrophilic amino acid or an amino acid having an aromatic ring, or an N-methylated amino acid thereof; X7 is W or a variant thereof; X8 is any hydrophilic amino acid or a variant thereof; X9 is W or a variant thereof; and X12 is C or a variant thereof.

[0260] In some embodiments, the peptides described herein have an amino acid sequence according to formula (Ib) or a pharmaceutically acceptable salt thereof, X1-X2-X4-X5-X7-X8-X9-X12 Formula (Ib) Wherein, X1 is any amino acid (e.g., a D-amino acid); X2 is an amino acid containing an aromatic ring or a variant thereof, or an N-methylated amino acid thereof; X4 is any hydrophobic amino acid or a variant thereof, X5 is a hydrophilic amino acid or a variant thereof; X7 is W or a variant thereof; X8 is an N-methylated amino acid; X9 is W or a variant thereof; and X12 is C or a variant thereof.

[0261] In some embodiments, the peptides described herein have an amino acid sequence according to formula (Ic) or a pharmaceutically acceptable salt thereof, X1-X2-X6-X7-X8-X9-X12 Formula (Ic) Wherein, X1 is any amino acid (e.g., a D-amino acid); X2 is an amino acid containing an aromatic ring or a variant thereof, or an N-methylated amino acid thereof; X6 is an N-methyl amino acid; X7 is W or a variant thereof; X8 is an N-methyl amino acid; X9 is W or a variant thereof; and X12 is C or a variant thereof.

[0262] In some embodiments, the peptides having formula (I), (Ia), (Ib), and / or (Ic) are monocyclic. In some embodiments, the amino acid at X1 is combined with a substitution of cysteine or cysteine.

[0263] In some embodiments, the peptide or a salt thereof comprises an amino acid sequence that is at least 95% identical to a sequence selected from SEQ ID NOs: 1-171, or a sequence having up to 1, 2, 3, 4, or 5 substitutions by conservative variants compared to any one of the sequences selected from SEQ ID NOs: 1-171.

[0264] In some embodiments, the peptide or a salt thereof consists of an amino acid sequence selected from SEQ ID NOs: 1-171.

[0265] In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 1-122, 159-163, and 165-171, and the peptide has a cyclic structure that has a cysteine residue or a variant thereof at the 12th residue, and wherein the amino acid at X1 (e.g., a chloroacetylated amino acid) forms a covalent bond with the cysteine residue or a variant thereof at the 12th residue (e.g., by reacting the chloroacetyl group in the X1 amino acid with the cysteine residue or a variant thereof).

[0266] In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 123-149 and 164, and the peptide has a cyclic structure that has a cysteine residue or a variant thereof at the 10th residue, and wherein the amino acid at X1 (e.g., a chloroacetylated amino acid) forms a covalent bond with the cysteine residue or a variant thereof at the 10th residue.

[0267] In some embodiments, as determined by K in surface plasmon resonance (SPR) analysis d the peptide has a binding affinity for human EphA2 of at most 100 nM.

[0268] In some embodiments, as determined by K in surface plasmon resonance (SPR) analysis d the peptide has a binding affinity for human EphA2 of at most 1 nM.

[0269] In some embodiments, the peptides disclosed herein bind to the ligand-binding domain (LBD) of human EphA2.

[0270] In some embodiments, the peptides of the present disclosure have good contact with Asp53 and / or Glu157 of human EphA2 according to SEQ ID NO: 276. In some embodiments, the peptides of the present disclosure interact with Asp53 and / or Glu157 of human EphA2 according to SEQ ID NO: 276. In some embodiments, the peptides of the present disclosure interact with Asp53 and / or Glu157 of human EphA2 according to SEQ ID NO: 277. The interaction can be the formation of one or more hydrogen bonds, van der Waals interactions, dipole-dipole interactions, or π-π stacking interactions.

[0271] In some embodiments, the peptides of the present disclosure interact with human EphA2 at one or more residues selected from the following: Asp53, Met55, Asn57, Met59, Met66, Thr101, Arg103, Phe156, Glu157, Arg159, Val161, Val189, and Ala190. In some embodiments, the peptides of the present disclosure bind to Asp53 and Glu157 of human EphA2. In some embodiments, the amino acid residue X5 of formula (I) interacts with Glu157 of human EphA2. In some embodiments, the amino acid residue X6 of formula (I) interacts with Arg159 of human EphA2. In some embodiments, the amino acid residue X7 of formula (I) interacts with one or more of Phe156, Thr101, Asn57, Val161, Met59, Ala190, and Met66 of human EphA2. In some embodiments, the amino acid residue X9 of formula (I) interacts with one or more of Phe156, Arg103, and Val189. In some embodiments, the amino acid residue X11 of formula (I) interacts with Asp53 of human EphA2. In some embodiments, the amino acid residue X7 of formula (I) forms a π-π stacking interaction with Phe156 of human EphA2. In some embodiments, the amino acid residue X9 of formula (I) forms a π-π stacking interaction with Phe156 of human EphA2. In some embodiments, the amino acid residue X2 of formula (I) interacts with the backbone carbonyl of C70 of the human EphA2 protein via an intermolecular aromatic H-bond interaction.

[0272] In some embodiments, when the peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, the amino acid residue X2 of formula (I) is located less than from C70 of the human EphA2. In some embodiments, X2 is located less than from C70. In some embodiments, X2 is located less than Position. In some embodiments, X2 is located less than from C70.

[0273] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, the amino acid residue X7 of formula (I) is located less than from Phe156 of the human EphA2. In some embodiments, X7 is located less than from Phe156. In some embodiments, X7 is located less than from Phe156.

[0274] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, the amino acid residue X7 of formula (I) is located less than from Thr101 of the human EphA2. In some embodiments, X7 is located less than from Thr101. In some embodiments, X7 is located less than from Thr101. In some embodiments, X7 is located less than from Thr101. In some embodiments, X7 is located less than from Thr101.

[0275] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, the amino acid residue X7 of formula (I) is located less than from Asn57 of the human EphA2. In some embodiments, X7 is located less than from Asn57. In some embodiments, X7 is located less than from Asn57. In some embodiments, X7 is located less than from Asn57. In some embodiments, X7 is located less than from Asn57.

[0276] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, the amino acid residue X7 of formula (I) is located less than from Val161 of the human EphA2. In some embodiments, X7 is located less than from Val161. In some embodiments, X7 is located less than from Val161. In some embodiments, X7 is located less than from Val161. In some embodiments, X7 is located less than Position.

[0277] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, the amino acid residue X7 of formula (I) is located less than from Met59 of the human EphA2. In some embodiments, X7 is located less than from Met59. In some embodiments, X7 is located less than from Met59. In some embodiments, X7 is located less than from Met59. In some embodiments, X7 is located less than from Met59.

[0278] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, the amino acid residue X7 of formula (I) is located less than from Ala190 of the human EphA2. In some embodiments, X7 is located less than from Ala190. In some embodiments, X7 is located less than from Ala190. In some embodiments, X7 is located less than from Ala190. In some embodiments, X7 is located less than from Ala190.

[0279] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, the amino acid residue X7 of formula (I) is located less than from Met66 of the human EphA2. In some embodiments, X7 is located less than from Met66. In some embodiments, X7 is located less than from Met66. In some embodiments, X7 is located less than from Met66. In some embodiments, X7 is located less than from Met66.

[0280] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, the amino acid residue X9 of formula (I) is located less than from Phe156 of the human EphA2. In some embodiments, X9 is located less than from Phe156. In some embodiments, X9 is located less than from Phe156.

[0281] In some embodiments, when the peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, the amino acid residue X9 of formula (I) is located less than from Asn3 of the human EphA2. In some embodiments, X9 is located less than from Asn3. In some embodiments, X9 is located less than from Asn3. In some embodiments, X9 is located less than from Asn3.

[0282] In some embodiments, when the peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, the amino acid residue X9 of formula (I) is located less than from Arg103 of the human EphA2. In some embodiments, X9 is located less than from Arg103. In some embodiments, X9 is located less than from Arg103. In some embodiments, X9 is located less than from Arg103.

[0283] In some embodiments, when the peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, the amino acid residue X9 of formula (I) is located less than from Val189 of the human EphA2. In some embodiments, X9 is located less than from Val189. In some embodiments, X9 is located less than from Val189. In some embodiments, X9 is located less than from Val189.

[0284] In some embodiments, when the peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, the amino acid residue X8 of formula (I) is located less than from Phe156 of the human EphA2. In some embodiments, X8 is located less than from Phe156. In some embodiments, X8 is located less than from Phe156.

[0285] In some embodiments, when the peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, the amino acid residue X2 of formula (I) is located less than from C70 of the human EphA2. In some embodiments, X2 is located less than from C70. In some embodiments, X2 is located less than position. In some embodiments, X2 is located less than from C70.

[0286] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, amino acid residue X7 of formula (I) is located less than from Phe156 of the human EphA2. In some embodiments, X7 is located less than from Phe156. In some embodiments, X7 is located less than from Phe156.

[0287] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, amino acid residue X9 of formula (I) is located less than from Thr101 of the human EphA2. In some embodiments, X9 is located less than from Thr101. In some embodiments, X9 is located less than from Thr101. In some embodiments, X9 is located less than from Thr101. In some embodiments, X9 is located less than from Thr101.

[0288] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, amino acid residue X8 of formula (I) is located less than from Asn57 of the human EphA2. In some embodiments, X8 is located less than from Asn57. In some embodiments, X8 is located less than from Asn57. In some embodiments, X8 is located less than from Asn57. In some embodiments, X8 is located less than from Asn57.

[0289] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, amino acid residue X7 of formula (I) is located less than from Val161 of the human EphA2. In some embodiments, X7 is located less than from Val161. In some embodiments, X7 is located less than from Val161. In some embodiments, X7 is located less than Position. In some embodiments, X7 is located less than from Val161.

[0290] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, the amino acid residue X7 of formula (I) is located less than from Met59 of the human EphA2. In some embodiments, X7 is located less than from Met59. In some embodiments, X7 is located less than from Met59. In some embodiments, X7 is located less than from Met59. In some embodiments, X7 is located less than from Met59.

[0291] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, the amino acid residue X7 of formula (I) is located less than from Ala190 of the human EphA2. In some embodiments, X7 is located less than from Ala190. In some embodiments, X7 is located less than from Ala190. In some embodiments, X7 is located less than from Ala190. In some embodiments, X7 is located less than from Ala190.

[0292] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, the amino acid residue X7 of formula (I) is located less than from Met66 of the human EphA2. In some embodiments, X7 is located less than from Met66. In some embodiments, X7 is located less than from Met66. In some embodiments, X7 is located less than from Met66. In some embodiments, X7 is located less than from Met66.

[0293] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, the amino acid residue X2 of formula (I) is located less than from Arg103 of the human EphA2. In some embodiments, X2 is located less than from Arg103. In some embodiments, X2 is located less than The position. In some embodiments, X2 is located less than from Arg103.

[0294] In some embodiments, when a peptide of formula (I) or a conjugate comprising the peptide binds to human EphA2, the amino acid residue X9 of formula (I) is located less than from Val189 of the human EphA2. In some embodiments, X9 is located less than from Val189. In some embodiments, X9 is located less than from Val189. In some embodiments, X9 is located less than from Val189.

[0295] In certain embodiments, the peptide has a plasma half-life (T 1 / 2 ) of at least 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 minutes as determined in vitro in human plasma at 37 °C. In certain embodiments, the peptide has a plasma half-life (T 1 / 2 ) of at least 250 minutes as determined in vitro in human plasma at 37 °C.

[0296] In some embodiments, the conjugate of the present disclosure has the structure of formula (III-1), wherein -linker- represents a linker.

[0297] In some embodiments, a conjugate comprising a cyclic peptide of formula (I) has the structure of formula (III-2), wherein X1-X12 have the above definitions, and Lcyc is a closed-loop group covalently connecting X1 and X12; and -linker- represents a linker.

[0298] In some embodiments, Lcyc is a group selected from Table 4B. In some embodiments, Lcyc is formed by the reaction of the first and second functional groups in Table 4C. In some embodiments, Lcyc is -C(=O)-CH2-. In some embodiments, Lcyc is -C(=O)-CH2-, which is formed by the reaction of a chloroacetylated (or bromoacetylated) amino acid with cysteine. In some embodiments, Lcyc is -C(=O)-CH2-S-, which is formed by the reaction of a chloroacetylated (or bromoacetylated) amino acid with an amino acid containing an SH group.

[0299] In some embodiments, the peptides or pharmaceutically acceptable salts thereof disclosed herein have a cyclic structure having an amino acid (e.g., a chloroacetylated amino acid) at the first residue X1 and a cysteine residue or variant thereof, and wherein the amino acid at X1 (e.g., the chloroacetylated amino acid) binds to the cysteine residue or variant thereof. In some embodiments, the peptides or pharmaceutically acceptable salts thereof disclosed herein have a cyclic structure having an amino acid (e.g., a chloroacetylated amino acid) at the first residue X1 and a cysteine residue or variant thereof, and wherein the amino acid at X1 (e.g., the chloroacetylated amino acid) forms a covalent bond with the cysteine residue or variant thereof. In some embodiments, the peptides or pharmaceutically acceptable salts thereof disclosed herein have a cyclic structure having a bromoacetylated amino acid at the first residue X1 and a cysteine residue or variant thereof, and wherein the bromoacetylated amino acid at X1 forms a covalent bond with the cysteine residue or variant thereof.

[0300] In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 1-122, 159-163, and 165-171, and the peptide has a cyclic structure having a cysteine residue or variant thereof at the 12th residue (X12). In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 1-122, 159-163, and 165-171, and the peptide has a cyclic structure having a cysteine residue or variant thereof at the 12th residue (X12), and wherein the chloroacetylated amino acid forms a covalent bond with the cysteine residue or variant thereof at the 12th residue. In some embodiments, the chloroacetyl group can be replaced by a bromoacetyl group.

[0301] In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 123-149 and 164, and the peptide has a cyclic structure having a cysteine residue or variant thereof at the 10th residue (X10). In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 123-149 and 164, and the peptide has a cyclic structure having a cysteine residue or variant thereof at the 10th residue (X10), and wherein the amino acid at X1 (e.g., the chloroacetylated amino acid) forms a covalent bond with the cysteine residue or variant thereof at the 10th residue. In some embodiments, the chloroacetyl group can be replaced by a bromoacetyl group.

[0302] In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 150 - 157, and the peptide has a cyclic structure that has a cysteine residue or a variant thereof at the 8th residue (X8). In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 150 - 157, and the peptide has a cyclic structure that has a chloroacetylated amino acid and a cysteine residue or a variant thereof at the 8th residue (X8), and wherein the chloroacetylated amino acid forms a covalent bond with the cysteine residue or a variant thereof at the 8th residue. In some embodiments, the chloroacetyl group can be replaced by a bromoacetyl group.

[0303] In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NO: 158, and the peptide has a cyclic structure that has a cysteine residue or a variant thereof at the 7th residue (X7). In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NO: 158, and the peptide has a cyclic structure that has a chloroacetylated amino acid and a cysteine residue or a variant thereof at the 7th residue (X7), and wherein the chloroacetylated amino acid forms a covalent bond with the cysteine residue or a variant thereof at the 7th residue. In some embodiments, the chloroacetyl group can be replaced by a bromoacetyl group.

[0304] In some embodiments, the peptides or pharmaceutically acceptable salts thereof disclosed herein have a cyclic structure in which the first amino acid is covalently linked to the last amino acid.

[0305] In some embodiments, the peptide or a pharmaceutically acceptable salt thereof has a cyclic structure having a chloroacetylated amino acid and a cysteine or substituted cysteine residue at X1, and wherein the chloroacetylated amino acid at X1 is bonded to the cysteine or substituted cysteine. In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NO:1-171. In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NO:1-171 and the peptide has a cyclic structure. In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NO:1-171 and the peptide has a cyclic structure having a chloroacetylated amino acid and a cysteine or substituted cysteine residue at the C-terminus, and wherein the chloroacetylated amino acid is bonded to the cysteine or substituted cysteine at the C-terminus. In some embodiments, the peptide has a cyclic structure comprising a chloroacetylated amino acid and; (i) a cysteine or substituted cysteine residue at the 12th residue, and wherein the chloroacetylated amino acid is bonded to the cysteine or substituted cysteine at the 12th residue; or (ii) a cysteine or substituted cysteine residue at the 10th residue, and wherein the chloroacetylated amino acid is bonded to the cysteine or substituted cysteine at the 10th residue. In some embodiments, the chloroacetyl group can be replaced by a bromoacetyl group.

[0306] For example, the cyclic peptide having formula (I) can have a structure as shown below For example, the cyclic peptide having formula (I) can have a structure as shown below

[0307] In some embodiments, the conjugate comprising the cyclic peptide having formula (I) has the following structure

[0308] In some embodiments, the conjugate of the present disclosure has the following structure wherein represents a linker.

[0309] In some embodiments, the peptide or a salt thereof comprises an amino acid sequence that is at least 95% identical to a sequence selected from the following SEQ ID NOs: (1) X1-X12 of SEQ ID NOs: 1-122, 159-163, and 165-171, (2) X1-X10 of SEQ ID NOs: 123-149 and 164, (3) X1-X8 of SEQ ID NOs: 150-157, and (4) X1-X7 of SEQ ID NO: 158. In some embodiments, the peptide or a salt thereof comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, or 98% identical to a sequence selected from the following SEQ ID NOs: (1) X1-X12 of SEQ ID NOs: 1-122, 159-163, and 165-171, (2) X1-X10 of SEQ ID NOs: 123-149 and 164, (3) X1-X8 of SEQ ID NOs: 150-157, and (4) X1-X7 of SEQ ID NO: 158. In some embodiments, the peptide or a salt thereof consists of an amino acid sequence selected from the following SEQ ID NOs: (1) X1-X12 of SEQ ID NOs: 1-122, 159-163, and 165-171, (2) X1-X10 of SEQ ID NOs: 123-149 and 164, (3) X1-X8 of SEQ ID NOs: 150-157, and (4) X1-X7 of SEQ ID NO: 158. In some embodiments, the peptide or a salt thereof comprises an amino acid sequence that differs from a sequence selected from the following SEQ ID NOs by at most 1, 2, 3, 4, or 5 amino acid residues: (1) X1-X12 of SEQ ID NOs: 1-122, 159-163, and 165-171, (2) X1-X10 of SEQ ID NOs: 123-149 and 164, (3) X1-X8 of SEQ ID NOs: 150-157, and (4) X1-X7 of SEQ ID NO: 158. In some embodiments, the peptide or a salt thereof comprises an amino acid sequence that has at most 1, 2, 3, 4, or 5 additions, deletions, and / or substitutions (including conservative substitutions) relative to a sequence selected from the following SEQ ID NOs: (1) X1-X12 of SEQ ID NOs: 1-122, 159-163, and 165-171, (2) X1-X10 of SEQ ID NOs: 123-149 and 164, (3) X1-X8 of SEQ ID NOs: 150-157, and (4) X1-X7 of SEQ ID NO: 158.In some embodiments, the peptide or a salt thereof comprises an amino acid sequence that has at most 1 addition, deletion, or substitution (including conservative substitutions) relative to a sequence selected from the following SEQ ID NOs: (1) X1-X12 of SEQ ID NOs: 1-122, 159-163, and 165-171, (2) X1-X10 of SEQ ID NOs: 123-149 and 164, (3) X1-X8 of SEQ ID NOs: 150-157, and (4) X1-X7 of SEQ ID NO: 158.

[0310] Exemplary peptides of the present disclosure include the peptides described in Table 1. In some embodiments, the peptides in Table 1 have a -C(=O)-halogen group attached to the N-terminus. In some embodiments, the peptides in Table 1 have a -C(=O)-CH2-halogen group attached to the N-terminus. In some embodiments, the peptides in Table 1 have a -C(=O)-halogen group attached at residue position 1 (e.g., X1). In some embodiments, the peptides in Table 1 have a -C(=O)-CH2-halogen group attached at residue position 1 (e.g., X1). In some embodiments, the peptides in Table 1 have a -C(=O)-Cl group attached to the N-terminus. In some embodiments, the peptides in Table 1 have a -C(=O)-CH2-Cl group attached to the N-terminus. In some embodiments, the peptides in Table 1 have a -C(=O)-Cl group attached at residue position 1 (e.g., X1). In some embodiments, the peptides in Table 1 have a -C(=O)-CH2-Cl group attached at residue position 1 (e.g., X1). In some embodiments, the peptides in Table 1 have a -C(=O)-Br group attached at residue position 1 (e.g., X1). In some embodiments, the peptides in Table 1 have a -C(=O)-CH2-Br group attached at residue position 1 (e.g., X1).

[0311] In some embodiments, the conjugates of the present disclosure have a -C(=O)-halogen group attached to the N-terminus. In some embodiments, the conjugates of the present disclosure have a -C(=O)-CH2-halogen group attached to the N-terminus. In some embodiments, the conjugates of the present disclosure have a -C(=O)-halogen group attached at residue position 1 (e.g., X1). In some embodiments, the conjugates of the present disclosure have a -C(=O)-CH2-halogen group attached at residue position 1 (e.g., X1). In some embodiments, the conjugates of the present disclosure have a -C(=O)-Cl group attached to the N-terminus. In some embodiments, the conjugates of the present disclosure have a -C(=O)-CH2-Cl group attached to the N-terminus. In some embodiments, the conjugates of the present disclosure have a -C(=O)-Cl group attached at residue position 1 (e.g., X1). In some embodiments, the conjugates of the present disclosure have a -C(=O)-CH2-Cl group attached at residue position 1 (e.g., X1). In some embodiments, the conjugates of the present disclosure have a -C(=O)-Br group attached at residue position 1 (e.g., X1). In some embodiments, the conjugates of the present disclosure have a -C(=O)-CH2-Br group attached at residue position 1 (e.g., X1). In some embodiments, the peptide in the conjugates of the present disclosure is monocyclic.

[0313] In some embodiments, the peptide of the conjugates described herein is a monocyclic peptide, wherein the -C(=O)-Cl at residue position 1 (e.g., X1) forms a bond with cysteine at residue position 12 (e.g., X12). In some embodiments, the peptide of the conjugates described herein is a monocyclic peptide, wherein the -C(=O)-CH2-Cl at residue position 1 (e.g., X1) forms a bond with cysteine at residue position 12 (e.g., X12). In some embodiments, the peptide in the conjugates described herein is a monocyclic peptide having 12 amino acid residues forming a ring.

[0314] In some embodiments, the peptide of the conjugates described herein is a monocyclic peptide, wherein the -C(=O)-Cl at residue position 1 (e.g., X1) forms a bond with cysteine at residue position 10 (e.g., X10). In some embodiments, the peptide in the conjugates described herein is a monocyclic peptide having 10 amino acid residues forming a ring.

[0315] In one aspect, there is described herein a peptide that has an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide competes with a peptide having an amino acid sequence with one or several amino acid deletions, substitutions, and / or additions selected from the amino acids of SEQ ID NO:1 for binding to human EphA2. da-MeF-N-L-Hgl-MeF-W1Me-V-W1Me-T-E-C (SEQ ID NO:1) or a pharmaceutically acceptable salt thereof.

[0316] In one aspect, described herein is a peptide having an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide competes with a peptide having a structure of formula (I) as described herein (e.g., formula (I-1) and formula (I-2)) or a pharmaceutically acceptable salt thereof for binding to human EphA2.

[0317] In some embodiments, the peptide competes for binding to human EphA2 at one or more amino acid residues selected from: Asp53, Met55, Asn57, Met59, Met66, Thr101, Arg103, Phe156, Glu157, Arg159, Val161, Val189, and Ala190. In some embodiments, the peptide competes for binding to human EphA2 at one or more amino acid residues selected from: Asp53, Phe156, and Glu157. In some embodiments, the peptide competes for binding to human EphA2 at Asp53, Glu157, or both.

[0318] The structures of the exemplary unnatural amino acids that appear in Table 1 can be found in Table 3.

[0319] As described in Table 1 or other tables, the abbreviations have the following meanings:

[0320] Lowercase d represents a D-amino acid, e.g., dF refers to d-phenylalanine;

[0321] Me refers to a methyl group, e.g., MeG represents N-methyl-glycine;

[0322] Ala or A refers to alanine;

[0323] Arg or R refers to arginine;

[0324] Asn or N refers to asparagine;

[0325] Asp or D refers to aspartic acid;

[0326] Cys or C refers to cysteine;

[0327] Gln or Q refers to glutamine;

[0328] Gly or G refers to glycine;

[0329] His or H refers to histidine;

[0330] Ile or I refers to isoleucine;

[0331] Leu or L refers to leucine;

[0332] Lys or K refers to lysine;

[0333] Met or M refers to methionine;

[0334] Phe or F refers to phenylalanine;

[0335] Pro or P refers to proline;

[0336] Ser or S refers to serine;

[0337] Thr or T refers to threonine;

[0338] Trp or W refers to tryptophan;

[0339] Tyr or Y refers to tyrosine;

[0340] Val or V refers to valine;

[0341] Unless otherwise clearly stated in this specification, the abbreviations of non-natural amino acids are used with the following meanings: Ahp 2-aminoheptanoic acid; Alb 2-amino-3-ureidopropionic acid, such as (S)-2-amino-3-ureidopropionic acid (CAS No. 1483-07-4); Da or da 2-aminopropionic acid, such as (2R)-2-aminopropionic acid; dkCOpipzaa 2-amino-6-{[4-(carboxymethyl)piperazine-1-carbonyl]amino}hexanoic acid, such as (2R)-2-amino-6-{[4-(carboxymethyl)piperazine-1-carbonyl]amino}hexanoic acid Dahp 2-aminoheptanoic acid, such as (2R)-2-aminoheptanoic acid df3CON 2-amino-3-(3-carbamoylphenyl)propionic acid, such as (2R)-2-amino-3-(3-carbamoylphenyl)propionic acid (CAS No. 1217637-40-5) MeF 2-(methylamino)-3-phenylpropionic acid, such as (2S)-2-(methylamino)-3-phenylpropionic acid; Me3Py 2-(methylamino)-3-(pyridin-3-yl)propionic acid, such as (2S)-2-(methylamino)-3-(pyridin-3-yl)propionic acid (CAS No. 1979173-93-7) Nal1 1-naphthylalanine; 4Py 2-Amino-3-(pyridin-4-yl)propanoic acid, such as (2S)-2-amino-3-(pyridin-4-yl)propanoic acid (CAS No. 169555-95-7) MeHph 2-(Methylamino)-4-phenylbutanoic acid, such as (2S)-2-(methylamino)-4-phenylbutanoic acid (CAS No. 1065076-30-3); W7N 2-Amino-3-{1H-pyrrolo[2,3-b]pyridin-3-yl}propanoic acid, such as (2S)-2-amino-3-{1H-pyrrolo[2,3-b]pyridin-3-yl}propanoic acid (CAS No. 737007-45-3) QPh 2-Amino-4-(phenylcarbamoyl)butanoic acid, such as (2S)-2-amino-4-(phenylcarbamoyl)butanoic acid (CAS No. 198134-12-2); MeF3CN 3-(3-Cyanophenyl)-2-(methylamino)propanoic acid, such as (2S)-3-(3-cyanophenyl)-2-(methylamino)propanoic acid (CAS No. 2642331-80-2) MeF3H 3-(3-Hydroxyphenyl)-2-(methylamino)propanoic acid, such as (2S)-3-(3-hydroxyphenyl)-2-(methylamino)propanoic acid alT 2-Amino-3-hydroxybutanoic acid, such as (2S,3S)-2-amino-3-hydroxybutanoic acid; W1Me 2-Amino-3-(1-methyl-1H-indol-3-yl)propanoic acid, such as (2S)-2-amino-3-(1-methyl-1H-indol-3-yl)propanoic acid (CAS No. 1334509-86-2) tma 2-Amino-4,4-dimethylpentanoic acid, such as (R)-2-amino-4,4-dimethylpentanoic acid Cbg 2-Amino-2-cyclobutylacetic acid, such as (S)-2-amino-2-cyclobutylacetic acid (CAS No. 1391630-31-1) Chg 2-Amino-2-cyclohexylacetic acid, such as (2S)-2-amino-2-cyclohexylacetic acid (CAS No. 161321-36-4) Cba 2-Amino-3-cyclobutylpropanoic acid, such as (2S)-2-amino-3-cyclobutylpropanoic acid (CAS No. 478183-62-9) KCOpipzaa 2-Amino-6-{[4-(carboxymethyl)piperazine-1-carbonyl]amino}hexanoic acid, e.g., (2S)-2-Amino-6-{[4-(carboxymethyl)piperazine-1-carbonyl]amino}hexanoic acid Hgn 2-Amino-5-carbamoylvaleric acid, e.g., (2S)-2-Amino-5-carbamoylvaleric acid (CAS No. 1263046-43-0) Hph Homo-phenylalanine; Nmm 2-Amino-3-(methylcarbamoyl)propanoic acid, e.g., (2S)-2-Amino-3-(methylcarbamoyl)propanoic acid (CAS No. 149204-93-3) Ndm 2-Amino-3-(dimethylcarbamoyl)propanoic acid, e.g., (2S)-2-Amino-3-(dimethylcarbamoyl)propanoic acid (CAS No. 138585-02-1) Hcit or hCit 2-Amino-6-(carbamoylamino)hexanoic acid, e.g., (2S)-2-Amino-6-(carbamoylamino)hexanoic acid (CAS No. 201485-17-8) Q Reduced glucosamine 2-Amino-4-{[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]carbamoyl}butanoic acid, e.g., (2S)-2-Amino-4-{[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]carbamoyl}butanoic acid mBph 3-Phenylphenylalanine; MeE 2-(Methylamino)pentanedioic acid, e.g., (2S)-2-(Methylamino)pentanedioic acid; MeN 3-Carbamoyl-2-(methylamino)propanoic acid, e.g., (2S)-3-Carbamoyl-2-(methylamino)propanoic acid; MeF4C 3-(4-Chlorophenyl)-2-(methylamino)propanoic acid, e.g., (2S)-3-(4-Chlorophenyl)-2-(methylamino)propanoic acid (CAS No. 1217779-77-5); Hph 2-Amino-4-phenylbutanoic acid, e.g., (2S)-2-Amino-4-phenylbutanoic acid; W1Me7N 2-Amino-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}propanoic acid, e.g., (2S)-2-amino-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}propanoic acid (CAS No. 1813528-10-7) W1Me7Cl 2-Amino-3-(7-chloro-1-methyl-1H-indol-3-yl)propanoic acid, e.g., (2S)-2-amino-3-(7-chloro-1-methyl-1H-indol-3-yl)propanoic acid W6C 6-Chlorotryptophan; 3Py6NH2 2-Amino-3-(6-aminopyridin-3-yl)propanoic acid, e.g., (2S)-2-amino-3-(6-aminopyridin-3-yl)propanoic acid Cit 2-Amino-5-(carbamoylamino)pentanoic acid, e.g., (2S)-2-amino-5-(carbamoylamino)pentanoic acid F23dMe 2-Amino-3-(2,3-dimethylphenyl)propanoic acid, e.g., (2S)-2-amino-3-(2,3-dimethylphenyl)propanoic acid (CAS No. 1270295-08-3) F3C 3-Chlorophenylalanine; Har 2-Amino-6-carbamimidoylhexanoic acid, e.g., (2S)-2-amino-6-carbamimidoylhexanoic acid (CAS No. 776277-76-0); bA 3-Aminopropanoic acid; Kac or KAc (2S)-2-Amino-6-acetamidohexanoic acid (CAS No. 159766-56-0); dkAc (2R)-2-Amino-6-acetamidohexanoic acid (CAS No. 320410-22-8); CdMe (R)-2-Amino-3-mercapto-3-methylbutanoic acid; C3SMe (2R,3S)-2-Amino-3-mercaptobutanoic acid; C3RMe (2R,3R)-2-Amino-3-mercaptobutanoic acid; 4Py2NH2 (S)-2-Amino-3-(2-aminopyridin-4-yl)propanoic acid; Hgl (S)-2-Aminoadipic acid.

[0342] The molecular weight of the described peptide can vary. In some embodiments, the peptide has a molecular weight of about 0.1 to about 25 kDa. In some embodiments, the peptide has a molecular weight of about 0.2 to about 20 kDa, about 0.5 to about 15 kDa, about 0.75 to about 10 kDa, about 0.5 to about 10 kDa, about 0.5 to about 5 kDa, about 0.5 to about 2.5 kDa, about 0.5 to about 2 kDa, about 0.5 to about 1.5 kDa, about 0.5 to about 1 kDa, about 1 to about 10 kDa, about 1 to about 5 kDa, about 1 to about 2.5 kDa, about 1 to about 2 kDa, about 1 to about 1.5 kDa, about 1 to about 1.25 kDa, or about 0.5 to about 1.25 kDa. In some embodiments, the peptide has a molecular weight of about 0.5 to 5 kDa. In some embodiments, the peptide has a molecular weight of about 0.5 to 2 kDa. In some embodiments, the peptide has a molecular weight of about 0.75 to 1.75 kDa. In some embodiments, the peptide has a molecular weight of about 1 to 1.5 kDa. In some embodiments, the peptide is monocyclic.

[0343] The peptides described herein can be cyclized (i.e., macrocyclized). Cyclization can be achieved less desirably via a single disulfide bond, or more desirably via: peptide bonds, alkyl bonds, alkenyl bonds, ester bonds, thioester bonds, ether bonds, thioether bonds, phosphoether bonds, azo bonds, C—S—C bonds, C—N—C bonds, C═N—C bonds, C═N—O bonds, amide bonds, lactam bridges, carbamoyl bonds, urea bonds, thiourea bonds, amine bonds, thioamide bonds, etc., but not limited to them. In some embodiments, the peptide is a cyclic peptide cyclized by: peptide bonds, alkyl bonds, alkenyl bonds, ester bonds, thioester bonds, ether bonds, thioether bonds, phosphoester ether bonds, azo bonds, C—N—C bonds, C═N—C bonds, C═N—O bonds, amide bonds, lactam bridges, carbamoyl bonds, urea bonds, thiourea bonds, amine bonds or thioamide bonds. In some embodiments, the cyclic peptide is cyclized via a thioether bond. In some embodiments, the cyclic peptide is cyclized via an oxime cyclization reaction. Cyclization of the peptide can sometimes stabilize the peptide structure and thus enhance the affinity for the target. Cyclization can occur between the N-terminus and the C-terminus, or it can occur between a terminal amino acid and a non-terminal amino acid. In some embodiments, cyclization occurs between two non-terminal amino acids. In some embodiments, the peptide is cyclized via oxime cyclization. In some embodiments, the peptide is cyclized between a cysteine and a haloacyl group. In some embodiments, the peptide contains a haloacetyl group (e.g., chloroacetyl or bromoacetyl) at the N-terminus. In some embodiments, the peptide contains a haloacetyl group (e.g., chloroacetyl or bromoacetyl) at the C-terminus. In some embodiments, the peptide contains Cys at the C-terminus. In some embodiments, the peptide contains Cys at the N-terminus. In some embodiments, cyclization occurs via a thioether bond between a Cys and a haloacetyl group. In some embodiments, cyclization occurs between the N-terminus and the C-terminus of the peptide.

[0344] As amino acids for macrocyclization, for example, amino acids having the following functional group A and amino acids having the corresponding functional group B can be used (see Table 4A). Functional group A or functional group B can be located on the N-terminal side. The amino acid having functional group A and the amino acid having functional group B can each be an N-terminal amino acid, a C-terminal amino acid or a non-terminal amino acid. In some embodiments, the amino acid having functional group A is located at the N-terminus. In some embodiments, the amino acid having functional group A is located at the C-terminus. In some embodiments, the amino acid having functional group A is located at a non-terminal amino acid. In some embodiments, the amino acid having functional group B is located at the N-terminus. In some embodiments, the amino acid having functional group B is located at the C-terminus. In some embodiments, the amino acid having functional group B is located at a non-terminal amino acid.

[0345] In some embodiments, as the amino acid (I-A), for example, chloroacetylated amino acids can be used. Examples of chloroacetylated amino acids include N-chloroacetyl-L-alanine, N-chloroacetyl-L-phenylalanine, N-chloroacetyl-L-tyrosine, N-chloroacetyl-L-tryptophan, N-3-(2-chloroacetamido)benzoyl-L-phenylalanine, N-3-(2-chloroacetamido)benzoyl-L-tyrosine, N-3-(2-chloroacetamido)benzoyl-L-tryptophan, β-N-chloroacetyl-L-diaminopropionic acid, γ-N-chloroacetyl-L-diaminobutyric acid, σ-N-chloroacetyl-L-ornithine, ε-N-chloroacetyl-L-lysine, N-3-chloromethylbenzoyl-L-tyrosine, N-3-chloromethylbenzoyl-L-tryptophan, and their corresponding D-amino acid derivatives (e.g., N-chloroacetyl-D-alanine, N-chloroacetyl-D-phenylalanine, N-chloroacetyl-D-tyrosine, and N-chloroacetyl-D-tryptophan). Table 4A. Functional groups for cyclization

[0346] Examples of the amino acid (I-B) include, but are not limited to: cysteine, homocysteine, mercaptopronvaline, mercaptopronleucine, 2-amino-7-mercaptoheptanoic acid, 2-amino-8-mercaptooctanoic acid, and amino acids obtained by protecting the SH groups of these amino acids and then removing the protecting groups, and their corresponding D-amino acid derivatives.

[0347] The cyclization method can be carried out, for example, according to the methods described in the following: Kawakami, T. et al., Nature Chemical Biology 5, 888-890 (2009); Yamagishi, Y. et al., ChemBioChem 10, 1469-1472 (2009); Sako, Y. et al., Journal of American Chemical Society 130, 7932-7934 (2008); or WO 2008 / 117833.

[0348] In some embodiments, for example, amino acids (II-A) selected from the following can be used: propargylglycine, homo-propargylglycine, 2-amino-6-heptynoic acid, 2-amino-7-octynoic acid, and 2-amino-8-nonynoic acid. Additionally, 4-pentynoyl- or 5-hexynoyl-acylated amino acids can also be used. Examples of 4-pentynoyl-acylated amino acids include N-(4-pentenoyl)-L-alanine, N-(4-pentenoyl)-L-phenylalanine, N-(4-pentenoyl)-L-tyrosine, N-(4-pentenoyl)-L-tryptophan, N-3-(4-pentynoyl-amido)benzoyl-L-phenylalanine, N-3-(4-pentynoyl-amido)benzoyl-L-tyrosine, N-3-(4-pentynoyl-amido)benzoyl-L-tryptophan, β-N-(4-pentenoyl)-L-diaminopropionic acid, γ-N-(4-pentenoyl)-L-diaminobutyric acid, σ-N-(4-pentenoyl)-L-ornithine, and ε-N-(4-pentenoyl)-L-lysine and their corresponding D-amino acid derivatives.

[0349] In some embodiments, for example, amino acids (II-B) selected from the following can be used: azidolalanine, 2-amino-4-azidobutyric acid, azido-norvaline, azido-norleucine, 2-amino-7-azidoheptanoic acid, and 2-amino-8-azidooctanoic acid. Additionally, azido-acetylated or 3-azidopentynoyl-acylated amino acids can also be used. Examples of azido-acetylated amino acids include N-azidoacetyl-L-alanine, N-azidoacetyl-L-phenylalanine, N-azidoacetyl-L-tyrosine, N-azidoacetyl-L-tryptophan, N-3-(4-pentynoyl-amido)benzoyl-L-phenylalanine, N-3-(4-pentynoyl-amido)benzoyl-L-tyrosine, N-3-(4-pentynoyl-amido)benzoyl-L-tryptophan, β-N-azidoacetyl-L-diaminopropionic acid, γ-N-azidoacetyl-L-diaminobutyric acid, α-N-azidoacetyl-L-ornithine, and ε-N-azidoacetyl-L-lysine and their corresponding D-amino acid derivatives.

[0350] The cyclization method can be carried out, for example, according to the methods described in the following: Sako, Y. et al., Journal of American Chemical Society 130, 7932 - 7934 (2008) or WO 2008 / 117833.

[0351] Examples of amino acids (III-A) include, but are not limited to, N-(4-aminomethyl-benzoyl)-phenylalanine (AMBF) and 4-3-aminomethyltyrosine.

[0352] Examples of amino acid (III-B) include, but are not limited to, 5-hydroxytryptophan (WoH). The cyclization method can be carried out, for example, according to the methods described in: Yamagishi, Y. et al., ChemBioChem [Chemistry and Biochemistry] 10, 1469-1472 (2009) or WO 2008 / 117833.

[0353] Examples of amino acid (IV-A) include, but are not limited to, 2-amino-6-chloro-hexynoic acid, 2-amino-7-chloro-heptynoic acid, and 2-amino-8-chloro-octynoic acid.

[0354] Examples of amino acid (IV-B) include, but are not limited to: cysteine, homocysteine, mercaptopronvaline, mercaptopronleucine, 2-amino-7-mercaptoheptanoic acid, and 2-amino-8-mercaptooctanoic acid, amino acids obtained by protecting the SH groups of these amino acids and then removing the protecting groups, and their corresponding D-amino acid derivatives. The cyclization method can be carried out, for example, according to the method described in WO2012 / 074129.

[0355] Examples of amino acid (V-A) include, but are not limited to, N-3-chloromethylbenzoyl-L-phenylalanine, N-3-chloromethylbenzoyl-L-tyrosine, and N-3-chloromethylbenzoyl-L-tryptophan.

[0356] Examples of amino acid (V-B) include, but are not limited to: cysteine, homocysteine, mercaptopronvaline, mercaptopronleucine, 2-amino-7-mercaptoheptanoic acid, and 2-amino-8-mercaptooctanoic acid, and amino acids obtained by protecting the SH groups of these amino acids and then removing the protecting groups, and their corresponding D-amino acid derivatives.

[0357] Amino acids I-A to V-A and I-B to V-B can be introduced into the peptide in a known manner by chemical synthesis or translation and synthesis as described herein. In some embodiments, the cyclization reaction involves forming a thioether bond using an amino acid containing a thioalkyl group (e.g., cysteine, homocysteine, mercaptopronvaline, mercaptopropylvaline, mercaptopronleucine, 2-amino-7-mercaptoheptanoic acid, and 2-amino-8-mercaptooctanoic acid).

[0358] The peptides described herein may contain one or more negatively charged amino acids and / or one or more positively charged amino acids. Positively charged amino acids include, for example, lysine, arginine, histidine, and amino acids containing an additional amine group. Positively charged amino acids may contain a heteroaryl substitution having one or more ring nitrogen atoms, such as pyridine, imidazole, pyrazole, or triazole. Negatively charged amino acids include, for example, amino acids containing an additional carboxylic acid group, such as glutamic acid, etc.

[0359] In some embodiments, the cyclic peptide having formula (I), formula (I-1), formula (I-2), formula (Ia), formula (Ib), or formula (Ic) has a net charge of -3 to +1. In some embodiments, the cyclic peptide has a net charge of -3. In some embodiments, the cyclic peptide has a net charge of -2. In some embodiments, the cyclic peptide has a net charge of -1. In some embodiments, the cyclic peptide has a net charge of 0. In some embodiments, the cyclic peptide has a net charge of +1. In some embodiments, the cyclic peptide having formula (I), formula (I-1), formula (I-2), formula (Ia), formula (Ib), or formula (Ic) has a net charge of at most -4. In some embodiments, the cyclic peptide has a net charge of -4. In some embodiments, the cyclic peptide having formula (I), formula (I-1), formula (I-2), formula (Ia), formula (Ib), or formula (Ic) has a net charge of at least +2. In some embodiments, the cyclic peptide has a net charge of +2. In some embodiments, the cyclic peptide has a net charge of +3. The net charge can be determined by summing the charges of each of the X1 to X12 amino acids (or each amino acid in the peptide). For example, aspartic acid (D) and glutamic acid (E) each have a charge of -1, lysine (K), arginine (R), and histidine (H) each have a charge of +1, and the remaining standard amino acids each have a charge of 0.

[0360] In some embodiments, the (cyclic) peptide having formula (I) has a net charge of -3 to +1. In some embodiments, the cyclic peptide has a net charge of -3. In some embodiments, the cyclic peptide has a net charge of -2. In some embodiments, the cyclic peptide has a net charge of -1. In some embodiments, the cyclic peptide has a net charge of 0. In some embodiments, the cyclic peptide has a net charge of +1. The net charge can be determined by summing the charges of each amino acid in the (cyclic) peptide.

[0361] In some embodiments, the (cyclic) peptides described herein (e.g., (cyclic) peptides having Formula (I), Formula (I-1), Formula (I-2), Formula (Ia), Formula (Ib), or Formula (Ic)) are configured to bind to EphA2 with a defined affinity, e.g., measured as a percentage of plasma protein albumin binding (PPB). The binding % can be determined by the HSA-HPLC method (measurement of drug-protein binding by immobilized human serum albumin-HPLC). The PPB can be determined in vitro by HPLC (e.g., Example B3) or other suitable methods known in the art. In some embodiments, 1% to 99% of the cyclic peptide binds to human serum albumin (HSA) in vitro as determined by HPLC under the conditions described in Example B3. In some embodiments, as determined by HPLC, about 2% to about 99%, about 5% to about 99%, about 10% to about 99%, about 20% to about 99%, about 30% to about 99%, about 40% to about 99%, about 50% to about 99%, about 60% to about 99%, about 70% to about 99%, or about 80% to about 99% of the cyclic peptide binds to HSA in vitro. In some embodiments, about 10% to about 95% of the cyclic peptide binds to HSA in vitro (i.e., about 10% to about 95% PPB). In some embodiments, about 20% to about 90% of the cyclic peptide binds to HSA in vitro. In some embodiments, about 20% to about 60% of the cyclic peptide binds to HSA in vitro. In some embodiments, about 40% to about 95% of the cyclic peptide binds to HSA in vitro. In some embodiments, about 40% to about 80% of the cyclic peptide binds to HSA in vitro. In some embodiments, about 40% to about 60% of the cyclic peptide binds to HSA in vitro. In some embodiments, about 60% to about 99% of the cyclic peptide binds to HSA in vitro. In some embodiments, about 60% to about 95% of the cyclic peptide binds to HSA in vitro. In some embodiments, about 60% to about 80% of the cyclic peptide binds to HSA in vitro. In some embodiments, about 60% to about 70% of the cyclic peptide binds to HSA in vitro. In some embodiments, about 40% to about 50% of the cyclic peptide binds to HSA in vitro. In some embodiments, about 50% to about 60% of the cyclic peptide binds to HSA in vitro. In some embodiments, about 70% to about 80% of the cyclic peptide binds to HSA in vitro. In some embodiments, about 80% to about 99% of the cyclic peptide binds to HSA in vitro. In some embodiments, about 80% to about 85% of the cyclic peptide binds to HSA in vitro.

[0362] In some embodiments, the conjugates described herein (e.g., conjugates comprising a (cyclic) peptide having Formula (I), Formula (I-1), Formula (I-2), Formula (Ia), Formula (Ib), or Formula (Ic)) are configured to bind to plasma proteins with a defined affinity, e.g., measured as the plasma protein albumin binding (PPB) percentage. PPB can be determined in vitro by HPLC (e.g., Example B3) or other suitable methods known in the art. In some embodiments, under the conditions described in Example B3, as determined by HPLC, 1% to 99% of the conjugate binds to human serum albumin (HSA) in vitro. In some embodiments, as determined by HPLC, about 2% to about 99%, about 5% to about 99%, about 10% to about 99%, about 20% to about 99%, about 30% to about 99%, about 40% to about 99%, about 50% to about 99%, about 60% to about 99%, about 70% to about 99%, or about 80% to about 99% of the conjugate binds to HSA in vitro. In some embodiments, about 10% to about 95% of the conjugate binds to HSA in vitro (i.e., about 10% to about 95% PPB). In some embodiments, about 20% to about 90% of the conjugate binds to HSA in vitro. In some embodiments, about 20% to about 60% of the conjugate binds to HSA in vitro. In some embodiments, about 40% to about 95% of the conjugate binds to HSA in vitro. In some embodiments, about 40% to about 80% of the conjugate binds to HSA in vitro. In some embodiments, about 40% to about 60% of the conjugate binds to HSA in vitro. In some embodiments, about 60% to about 99% of the conjugate binds to HSA in vitro. In some embodiments, about 60% to about 95% of the conjugate binds to HSA in vitro. In some embodiments, about 60% to about 80% of the conjugate binds to HSA in vitro. In some embodiments, about 60% to about 70% of the conjugate binds to HSA in vitro. In some embodiments, about 40% to about 50% of the conjugate binds to HSA in vitro. In some embodiments, about 50% to about 60% of the conjugate binds to HSA in vitro. In some embodiments, about 70% to about 80% of the conjugate binds to HSA in vitro. In some embodiments, about 80% to about 99% of the conjugate binds to HSA in vitro. In some embodiments, about 80% to about 85% of the conjugate binds to HSA in vitro.

[0363] In some embodiments, the (cyclic) peptide having Formula (I), Formula (I-1), Formula (I-2), Formula (Ia), Formula (Ib), or Formula (Ic) does not contain any S-S bonds.

[0364] In some embodiments, the peptides of the present disclosure can be cyclized by forming the groups shown in Table 4B. Table 4B. Closed-loop groups (m and n are independently integers from 0 or 1 to 6.)

[0365] In some embodiments, m is 0 and n is 0. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6.

[0366] In some embodiments, the peptides of the present disclosure (e.g., peptides having formula (I), (Ia), (Ib), and (Ic)) can be cyclized by reacting a first functional group with a second functional group, see Table 4C. In some embodiments, the first functional group is located at the N-terminus. In some embodiments, the first functional group is located at a non-terminal amino acid. In some embodiments, the second functional group is located at the C-terminus. In some embodiments, the second functional group is located at a non-terminal amino acid. Table 4C. Formation of closed-loop groups

[0367] In some embodiments, a conjugate comprising any of the peptides of Table 1 can further comprise amino acid residues at the N- and / or C-terminus of the peptide that are not part of the cyclic structure. In some embodiments, the conjugate further comprises a linker.

[0368] The peptides described herein can be peptidomimetics. For example, the peptide can contain non-peptide bonds and it can contain one or more non-natural amino acids. Unless otherwise specified, each of the amino acids in the peptides described herein (except for the natural amino acid glycine) can independently exist in its D or L form. Both the D and L forms are encompassed in the present disclosure.

[0369] In the present disclosure, the term "amino acid" encompasses amino acid derivatives. Derivatives include, for example, amino acids obtained by modifying the natural amino acids that make up proteins produced by biological substances encoded by cellular DNA. Examples of such non-natural amino acids include hydroxyproline and hydroxylysine (the hydroxyproline and hydroxylysine are amino acids with a hydroxy group introduced therein) and diaminopropionic acid (the diaminopropionic acid is an amino acid with an amino group introduced therein).

[0370] The peptides described herein may include N-substituted amino acids. In some embodiments, the N-substituted amino acid is a derivative of tryptophan, phenylalanine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, or valine. In some embodiments, the N-substitution is N-alkyl, such as N-methyl and N-ethyl. In some embodiments, the N-substitution is N-methyl. In some embodiments, the N-substitution is N-aryl, such as N-phenyl or N-biphenyl. In some embodiments, the N-substitution is N-heteroaryl, such as N-pyridyl. In some embodiments, the N-substituted amino acid is located at the N-terminus of the peptide. In some embodiments, the N-substituted amino acid is a non-terminal amino acid.

[0371] In some embodiments, the peptides described herein include one or more of the amino acids in Tables 5A to 5F. Table 5A. Exemplary Amino Acids at the N-Terminus or C-Terminus N-chloroacetyl-L-alanine acetyl-L-alanine N-chloroacetyl-L-phenylalanine acetyl-L-phenylalanine N-chloroacetyl-L-phenylalanine acetyl-L-tyrosine N-chloroacetyl-L-tyrosine acetyl-L-tryptophan N-chloroacetyl-L-tryptophan acetyl-D-alanine N-chloroacetyl-D-alanine acetyl-D-phenylalanine N-chloroacetyl-D-phenylalanine acetyl-D-tyrosine N-chloroacetyl-D-tyrosine acetyl-D-tryptophan N-chloroacetyl-D-tryptophan N-3-chloromethylbenzoyl-L-tyrosine N-3-chloromethylbenzoyl-L-tryptophan Table 5B. Exemplary Amino Acids Crosslinked to the Peptide Nγ-(2-chloroacetyl)-α,γ-diaminobutyric acid Nγ-(2-chloroacetyl)-α,γ-diaminopropionic acid Table 5C. D-Amino Acids D-serine D-phenylalanine D-tyrosine D-tryptophan Table 5D. Exemplary N-Alkyl Amino Acids Exemplary alkyl groups in Table 5D include methyl, ethyl, and propyl groups. Table 5E. Exemplary Peptidomimetic Blocks N-ethyl-glycine N-n-propyl-glycine N-n-butyl-glycine N-n-pentyl-glycine N-n-hexyl-glycine N-n-heptyl-glycine N-n-octyl-glycine N-isopentyl-glycine N-(2-phenylethyl)-glycine N-(3-phenylpropyl)-glycine N-[2-(p-hydroxyphenyl)ethyl]-glycine Table 5F. Exemplary Unnatural Amino Acids biphenylalanine p-trifluoromethylphenylalanine p-azidophenylalanine p-biotin-aminophenylalanine e-N-biotin-lysine e-N-acetyl-lysine L-citrulline L-5-hydroxytryptophan L-1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid amino isobutyric acid N-methyl-amino isobutyric acid N-methyl-phenylglycine

[0372] The amino acids used in the peptides of the present disclosure may be replaced by similar amino acids. In some embodiments, an amino acid may be replaced by another amino acid having similar hydrophobicity. In some embodiments, an amino acid may be replaced by another amino acid having similar hydrophilicity. In some embodiments, an amino acid may be replaced by another amino acid having similar size. In some embodiments, an amino acid may be replaced by another amino acid having similar charge. In some embodiments, an amino acid may be replaced by another amino acid having similar functional groups. In some embodiments, an amino acid may be replaced by another amino acid having the same functional group.

[0373] In some embodiments, the amino acids described herein can be replaced by their variants. Examples of amino acid substitutions or variants include derivatives having an amine, amide, ester, or carboxyl group as their C-terminus and / or N-terminus. Additional examples of amino acid / peptide variants include those obtained by modification such as phosphorylation, alkylation (e.g., methylation), acetylation, adenylylation, ADP-ribosylation, or glycosylation, as well as fusion proteins obtained by fusion with another peptide or protein. These variants can be prepared by those skilled in the art in known ways or methods based thereon. Amino acid variants further encompass amino acids having the same functional groups but different side-chain lengths (e.g., LysAc compared to OrnAc and cysteine compared to homocysteine). Amino acid variants further encompass amino acids having different aromatic moieties compared to standard amino acids (e.g., indole in tryptophan compared to 7-azaindole in 7-AzaTrp; phenyl in phenylalanine compared to pyridine in 4Py). Amino acid variants further encompass amino acids having optional substituents, i.e., optionally substituted amino acids. In some embodiments, the optionally substituted amino acids are optionally substituted by one or more substituents independently selected from the following: halogen, hydroxy, cyano, amino, amide, nitro, ureido, C1-C6 alkyl, C1-C6 alkoxy, C6-C 10 aryl, C3-C6 cycloalkyl, 6-10 membered heteroalkyl, and 6-10 membered heteroaryl. In some embodiments, the optionally substituted amino acids are optionally substituted by one or more substituents independently selected from the following: halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, oxo, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heteroalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, and aryl sulfone. In some embodiments, the substituents can include any of the substituents described herein, e.g.: halogen, hydroxy, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oxime (=N-OH), hydrazino (=N-NH2), SF 5 , -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(Ra ) 2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -O-R c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), and -R b -S(O) t N(R a )2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl and heterocycle, any of which may optionally be substituted by: alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo(=O), thioxo(=S), cyano(-CN), nitro(-NO2), imino(=N-H), oxime(=N-OH), hydrazine(=N-NH2), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -O-Rc -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), and -R b -S(O) t N(R a )2(where t is 1 or 2); where each R a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, and heterocycle, where each R a , where valence allows, may optionally be substituted with: alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo(=O), thioxo(=S), cyano(-CN), nitro(-NO2), imino(=N-H), oxime(=N-OH), hydrazine(=N-NH2), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -O-R c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a)C(O)R a 、 -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), and -R b -S(O) t N(R a )2 (where t is 1 or 2); and wherein each R b is independently selected from a direct bond or a straight-chain or branched alkylene, alkenylene or alkynylene chain, and each R c is a straight-chain or branched alkylene, alkenylene or alkynylene chain.

[0374] In some embodiments, variants of the amino acid are selected from amino acids having one, two or three amino acid-based substituents, and wherein these substituents are independently selected from halogen, -CN, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, oxo, -OH, -CO2H, -CO2-C1-C3 alkyl, -C(=O)NH2, -C(=O)NH(C1-C3 alkyl), -C(=O)N(C1-C3 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C3 alkyl), -S(=O)2N(C1-C3 alkyl)2, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C6-C 10 aryl, C3-C6 cycloalkyl, 6-10 membered heteroalkyl and 6-10 membered heteroaryl.

[0375] In some embodiments, the variant is selected from amino acids having one or two amino acid-based substituents, and wherein these substituents are independently selected from halogen, -CN, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, oxo, -OH, -CO2H, -CO2-C1-C3 alkyl, -C(=O)NH2, -C(=O)NH(C1-C3 alkyl), -C(=O)N(C1-C3 alkyl)2, and C1-C6 alkyl. In some embodiments, the variant is selected from amino acids having one or two amino acid-based substituents, and wherein these substituents are independently selected from halogen, -CN, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, and C1-C6 alkyl. In some embodiments, the variant is selected from amino acids having one or two amino acid-based substituents, and wherein these substituents are independently selected from C1-C6 alkyl.

[0376] In some embodiments, variants of an amino acid are selected from amino acids having similar hydrophilicity or hydrophobicity compared to the amino acid. Thus, in some embodiments, a positively charged amino acid can be a variant of another positively charged amino acid. In some embodiments, a negatively charged amino acid can be a variant of another negatively charged amino acid. In some embodiments, a zwitterionic amino acid can be a variant of another zwitterionic amino acid.

[0377] In some embodiments, hydrophilic amino acids have a charged side chain. In some embodiments, hydrophilic amino acids have a positive charge. In some embodiments, hydrophilic amino acids have a negative charge. In some embodiments, hydrophilic amino acids are zwitterionic (e.g., KCOpipzaa). In some embodiments, hydrophilic amino acids contain an -OH, COOH, -NH-, or NH2 moiety. In some embodiments, hydrophilic amino acids contain -OH, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3. In some embodiments, hydrophilic amino acids contain the following side chains: C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -C 0-6 alkylene-NH-C(=NH)-NH2, -C 0-6 alkylene-CO-NH2, -C 0-6 alkylene-COOH, or -NH-CO-C 1-6 alkyl.

[0378] In some embodiments, the hydrophobic amino acid is uncharged. In some embodiments, the hydrophobic amino acid comprises at least 2 consecutive carbon atoms. In some embodiments, the hydrophobic amino acid comprises at least 3 consecutive carbon atoms, which can be straight-chain or branched-chain. In some embodiments, the hydrophobic amino acid comprises at least 4 consecutive carbon atoms, which can be straight-chain or branched-chain. In some embodiments, the hydrophobic amino acid comprises at least 5 consecutive carbon atoms, which can be straight-chain or branched-chain. In some embodiments, the hydrophobic amino acid comprises an ethylidene moiety in the side chain. In some embodiments, the hydrophobic amino acid comprises a propylidene moiety in the side chain. In some embodiments, the hydrophobic amino acid comprises a butylidene moiety in the side chain. In some embodiments, the hydrophobic amino acid comprises a phenyl moiety. In some embodiments, the hydrophobic amino acid comprises a heteroaryl moiety. In some embodiments, the hydrophobic amino acid is Trp, Tyr, Phe or a derivative thereof.

[0379] In some embodiments, the variant of the amino acid is selected from amino acids having the same functional groups as the amino acid, and wherein the variant has a different side-chain length compared to the amino acid. In some embodiments, the variant of the amino acid is selected from amino acids having the same charge compared to the amino acid. In some embodiments, the variant of the amino acid is selected from amino acids having the same polarity compared to the amino acid. In some embodiments, an amino acid comprising an aromatic group can be a variant of another amino acid having an aromatic group. In some embodiments, an amino acid comprising a phenyl group can be a variant of another amino acid comprising a phenyl group. In some embodiments, an amino acid comprising a heteroaryl group can be a variant of another amino acid comprising a heteroaryl group. Amino acids having an aromatic group include, but are not limited to, F, W, Me3Py, MeF, MeF3H, MeFCN, MeF4F, MeF3F, MeFCON, F23dMe, df3CON, W1Me, W1Me7Cl, W1Me7N, W1Et, 7-AzaTrp, W1Me7Br, W1Me7OMe, W1Me6O7Cl, d4PyCON, W7Me, dDab-NH2-Ph3-SO2F, dDap-NH2-Ph3-SO2F, dDap-NH2-Ph4-SO2F, MeF4C, 4Py, 3Py6NH2, 4Py2NH2 and Me4Py. In some embodiments, an amino acid comprising a cycloalkyl group can be a variant of another amino acid having a cycloalkyl group. In some embodiments, an amino acid comprising a heterocycloalkyl group can be a variant of another amino acid having a heterocycloalkyl group.

[0380] In some embodiments, variants of the amino acid are selected from amino acids having a polarity and / or charge similar to that of the amino acid. For example, in some embodiments, a polar, uncharged amino acid can be a variant of another polar, uncharged amino acid (e.g., Hgn, Q, S, T, Q-reduced glucosamine),

[0381] In some embodiments, the variant of the amino acid has the same number of hydrogen donors as the amino acid. In some embodiments, the variant of the amino acid has the same number of hydrogen acceptors as the amino acid.

[0382] In some embodiments, the variant has a molecular weight that varies by no more than 14, 28, 30, 45, or 60 g / mol compared to the amino acid. In some embodiments, the variant has a molecular weight that varies by no more than 14 g / mol compared to the amino acid. In some embodiments, the variant has a molecular weight that varies by no more than 50 g / mol compared to the amino acid. In some embodiments, the variant has a molecular weight that varies by no more than 28 g / mol compared to the amino acid.

[0383] Amino acid variants further encompass amino acids in which a functional group is replaced by another functional group having similar properties. For example, cysteine can be replaced by homocysteine. In some embodiments, an aryl functional group can be replaced by an aryl or heteroaryl group. In some embodiments, a heteroaryl functional group can be replaced by an aryl or heteroaryl group. In some embodiments, an amino functional group can be replaced by NH(alkyl).

[0384] As used herein, the expression "conservative amino acid substitution" refers to the substitution of amino acids that are functionally equivalent or similar. Conservative amino acid substitutions in a peptide result in a static change in the amino acid sequence of the peptide. For example, one or two or more amino acids having similar polarities are functionally equivalent to each other and result in a static change in the amino acid sequence of the peptide. Generally, substitutions within a particular group can be considered conservative in terms of structure and function. However, as will be clear to those of ordinary skill in the art, the role played by a particular amino acid residue can be determined by its influence on the three-dimensional structure of the molecule containing the amino acid. For example, a cysteine residue in the oxidized (disulfide) form may have a lower polarity than a cysteine residue in the reduced (thiol) form. The long aliphatic portion of the arginine side chain may constitute a structurally and functionally important feature. In addition, side chains containing aromatic rings (tryptophan, tyrosine, phenylalanine) may contribute to ion-aromatic interactions or cation-π interactions. In such cases, even if the amino acids having these side chains are replaced by amino acids belonging to acidic or nonpolar groups, they may be conservative in terms of structure and function. Residues such as proline, glycine, cysteine (disulfide foam) may directly affect the three-dimensional structure of the backbone and generally cannot be replaced without structural distortion.

[0385] Conservative amino acid substitutions as shown below include specific substitutions based on side chain similarity (e.g., such substitutions are described in Lehninger, Biochemistry, 2nd revised edition, published in 1975, pages 73 to 75: L. Lehninger, Biochemistry, 2nd edition, pages 73 - 75, Worth Publishers, New York (1975), which is incorporated herein by reference) and typical substitutions.

[0386] Hydrophobic amino acids include amino acids that exhibit hydrophobicity and include alanine (also referred to as “Ala” or simply “A”), glycine (also referred to as “Gly” or simply “G”), valine (also referred to as “Val” or simply “V”), leucine (also referred to as “Leu” or simply “L”), isoleucine (also referred to as “Ile” or simply “I”), proline (also referred to as “Pro” or simply “P”), phenylalanine (also referred to as “Phe” or simply “F”), tryptophan (also referred to as “Trp” or simply “W”), tyrosine (also referred to as “Tyr” or simply “Y”), and methionine (also referred to as “Met” or simply “M”).

[0387] Exemplary hydrophobic amino acids can be further divided into the following groups: ● Aliphatic amino acids: Amino acids having a fatty acid or hydrogen in the side chain, including, for example, Ala, Gly, Val, Ile, and Leu. ● Aliphatic / branched - chain amino acids: Amino acids having a branched - chain fatty acid in the side chain, including, for example, Val, Ile, and Leu. ● Aromatic amino acids: Amino acids having an aromatic ring in the side chain, including, for example, Trp, Tyr, and Phe.

[0388] In some embodiments, the hydrophobic amino acid has 4 or more carbon atoms in the side chain (straight - chain, branched - chain, or cyclic carbon side chain), such as Leu, Hcit, Cbg, Chg, or Cba, each of which is optionally N - methylated.

[0389] Hydrophilic amino acids include amino acids that exhibit hydrophilicity, including, for example, serine (also referred to as "Ser" or simply "S"), threonine (also referred to as "Thr" or simply "T"), cysteine (also referred to as "Cys" or simply "C"), asparagine (also referred to as "Asn" or simply "N"), glutamine (also referred to as "Gln" or simply "Q"), aspartic acid (also referred to as "Asp" or simply "D"), glutamic acid (also referred to as "Glu" or simply "E"), lysine (also referred to as "Lys" or simply "K"), arginine (also referred to as "Arg" or simply "R"), and histidine (also referred to as "His" or "H").

[0390] Exemplary hydrophilic amino acids can be further divided into the following groups: ● Acidic amino acids: Amino acids whose side chains exhibit acidity, including Asp and Glu. ● Basic amino acids: Amino acids whose side chains exhibit basicity, including Lys, Arg, and His. ● Neutral amino acids: Amino acids whose side chains exhibit neutrality, including Ser, Thr, Asn, Gln, and Cys.

[0391] Exemplary hydrophilic amino acids include, for example, N, Q, K, G, S, T, E, Aib, Hcit, Cit, Hgn, KCOpipzaa, Har, Nmm, Ndm, Ala, Hgl, 3Py6NH2, or variants thereof (including D-amino acids, such as da and variants, such as Q-reduced glucosamine, which adds a glucosamine component to the NH2 terminus of its side chain).

[0392] In some embodiments, the peptides described herein contain amino acids that affect the backbone direction, such as, for example, Gly and Pro. In some embodiments, the peptides described herein contain sulfur-containing amino acids, such as, for example, Cys and Met. In some embodiments, the peptides described herein include amino acids containing an aromatic ring, which may be optionally substituted. Amino acids containing an aromatic ring include: for example, F (Phe; phenylalanine), Y (Tyr; tyrosine), W (Trp; tryptophan).

[0393] In some embodiments, W or its variant can be W, an amino acid having a heteroatom in the indole ring of W in the side chain, an amino acid in which the hydrogen of NH in the indole ring of W is substituted, or an amino acid having a substituent in the benzene ring of W, etc.

[0394] In some embodiments, F or its variant can be F (phenylalanine) (an amino acid), wherein: (i) the phenyl ring of F is substituted with 1 or 2 substituents independently selected from the following: -OH, -CN, -C 1-3An alkyl group, such as -CH3; (ii) a 6-membered heteroaryl ring optionally substituted with 1 or 2 substituents each independently selected from: –OH, -CN, -C 1-3 An alkyl group, such as -CH3; or (iii-1) having a heteroatom on a phenyl ring with F in the side chain; (iii-2) a derivative amino acid of F, wherein the 6-membered heteroaryl ring on the side chain is substituted; etc. In some aspects, F or its variant is optionally N-methylated.

[0395] In some embodiments, W, Y or their variants can be an amino acid of W, Y having a 6-membered aryl or heteroaryl, or a 9- or 10-membered bicyclic aryl or heteroaryl connected to the α-carbon (e.g., a methylene group) through carbon. In some embodiments, the 6-, 9- and 10-membered heteroaryls have one heteroatom (e.g., N), and wherein the 6-, 9- and 10-membered aryl or heteroaryl is optionally substituted with 1 or 2 substituents independently selected from: –methyl, -ethyl, -Cl and -F. In certain embodiments, W or Y or their variants are W1Me, W1Me7Cl, or F23dMe, Nal1, Nal2, W1Et, Nal21N, 3Bzf, 3Bzt, Nal15N, Nal14N, Nal24N, Nal28N, F23dC or W1Me7N. In some embodiments, a variant of W is W1Me. In some embodiments, a variant of W is W1Me7Cl. In some embodiments, a variant of Y is F23dMe.

[0396] In some embodiments, the amino acids described herein are N-alkylated.

[0397] In some embodiments, the amino acids described herein are not N-alkylated (e.g., amino acids with -H on the α-amino group). In certain embodiments, such amino acids are A, E, N, K, Q glucosamine, KCOpipzaa, Q, Hse, Cit, Hcit, KAc, DapAc, OrnAc, T, alT, Aib or 3Py6NH2, more preferably V, Q glucosamine, Cit, Hcit, K or 3Py6NH2.

[0398] Examples of amino acids include natural protein L-amino acids, unnatural amino acids, and chemically synthesized compounds having properties characteristic of amino acids known in the art. Examples of unnatural amino acids include, but are not limited to: α,α-disubstituted amino acids (such as α-methylalanine), N-alkyl-α-amino acids, D-amino acids, β-amino acids, and α-hydroxy acids, each having a backbone structure different from that of natural amino acids; amino acids having a side chain structure different from that of natural amino acids (such as norleucine and homohistidine); amino acids having an additional methylene group in their side chains (such as "homo" amino acids, homophenylalanine, and homohistidine); and amino acids obtained by replacing the carboxylic acid functional amino group in their side chains with a sulfonic acid group (such as sulfopropylalanine).

[0399] In some embodiments, the amino acids described herein are N-alkylated. In some embodiments, the amino acids described herein are not N-alkylated (e.g., amino acids bearing -H on the α-amino group). In certain embodiments, such amino acids are A, E, N, K, Q-reduced glucosamine, KCOpipzaa, Q, Hse, Cit, Hcit, KAc, DapAc, OrnAc, T, alT, Aib, or 3Py6NH2, more preferably V, Q-reduced glucosamine, Cit, Hcit, K, or 3Py6NH2.

[0400] The peptides described herein may include one or more unnatural amino acids. Unnatural amino acids include, but are not limited to: (1) amino acids corresponding to amino acid residues on a polypeptide that has been modified after expression (e.g., phosphorylated tyrosine, acetylated lysine, farnesylated cysteine), (2) amino acids that are naturally occurring but cannot be used for ribosomal expression, and (3) artificial amino acids that do not occur naturally (unnatural amino acids). Non-limiting examples of unnatural amino acids include: p-acetyl-L-phenylalanine, p-iodo-L-phenylalanine, p-methoxyphenylalanine, O-methyl-L-tyrosine, p-propargyloxyphenylalanine, p-propargyl-phenylalanine, L-3-(2-naphthyl)alanine, 3-methylphenylalanine, O-4-allyl-L-tyrosine, 4-propyl-L-tyrosine, tri-O-acetyl-GlcNAcp-serine, L-Dopa, fluorinated phenylalanine, isopropyl-L-phenylalanine, p-azido-L-phenylalanine, p-acyl-L-phenylalanine, p-benzoyl-L-phenylalanine, boronophenylalanine, O-propargyl tyrosine, L-phosphoserine, phosphonoserine, phosphonotyrosine, p-bromophenylalanine, selenocysteine, p-amino-L-phenylalanine, isopropyl-L-phenylalanine, and azidolysine (AzK). In some embodiments, the unnatural amino acid is an unnatural analog of a tyrosine amino acid; an unnatural analog of a glutamine amino acid; an unnatural analog of a phenylalanine amino acid; an unnatural analog of an alanine amino acid; an unnatural analog of a serine amino acid; an unnatural analog of a threonine amino acid; an alkyl, aryl, acyl, azido, cyano, halo, hydrazine, hydrazide, hydroxy, alkenyl, alkynyl, ether, thiol, sulfonyl, seleno, ester, thioacid, borate, boronate, phosphate, phosphonate, phosphine, heterocycle, enone, imine, aldehyde, hydroxylamine, ketone, or amino-substituted amino acid; or a combination thereof. In some embodiments, the unnatural amino acid is an amino acid having a photoactivatable crosslinker; a spin-labeled amino acid; a fluorescent amino acid; a metal-binding amino acid; a metal-containing amino acid; a photocaged and / or photo-isomerizable amino acid; an amino acid containing biotin or a biotin analog; a keto-containing amino acid; an amino acid containing polyethylene glycol or a polyether; a heavy atom-substituted amino acid; a chemically cleavable or photocleavable amino acid; an amino acid having an extended side chain; an amino acid containing a toxic group; a sugar-substituted amino acid; a carbon-linked sugar-containing amino acid; an amino acid having redox activity; an α-hydroxy-containing amino acid; an aminothioacid; an α,α-disubstituted amino acid; a β-amino acid; a cyclic amino acid other than proline or histidine, or an aromatic amino acid other than phenylalanine, tyrosine, or tryptophan.

[0401] Non-natural amino acids include, for example, N-alkyl amino acids, in which the above natural amino acids are N-alkylated, such as those modified with lower alkyl groups (e.g., C1 to C5, C1 to C3, and C1), where the nitrogen forming the peptide bond is branched or unbranched. Exemplary N-alkyl amino acids include, for example, N-ethyl amino acid, N-butyl amino acid, and N-methyl amino acid. Also included are amino acids in which a functional group is further added to the side chain of a natural amino acid or the functional group is replaced by another functional group (e.g., amino acids having a substitution or addition in a part of the side chain such as an arylene group, an alkylene group, etc.; amino acids in which the arylene group or alkyl group of the side chain has an increased number of C atoms; amino acids having a substitution in the aromatic ring of the side chain; heterocyclic or fused-ring amino acids; or the like). Exemplary N-alkyl amino acids further include, for example, N-alkyl lysine and N-methyl lysine. Exemplary N-alkyl amino acids further include, for example, N-methyl lysine to which an albumin conjugate is bound.

[0402] In a non-limiting manner, non-natural amino acids include but are not limited to N-methyl amino acid, da, kCOpipzaa, dahp, df3CON, 4Py, W7N, QPh, alT, W1Me, Cbg, Chg, Cba, Hgl, Hgn, Nmm, Ndm, Hcit, Q-reduced glucosamine, Hph, W1Me7N, W1Me7Cl, 3Py6NH2, Cit, F23dMe, Har, bA, Kac, dkAc, MeF, Me3Py, MeHph, MeF3CN, MeF3H, MeE, MeN, MeF4C, Nal1, Nal2, W1Et, Nal21N, 3Bzf, 3Bzt, al15N, Nal14N, Nal24N, Nal28N, F23dMe, F23dC, W1Me7N, W1Me7Cl, Hse, DapAc, OrnAc, Alb, etc. It should be noted that D-amino acids such as da can be classified as D-amino acids, but they can also be classified according to the characteristics of their side chains, and N-methyl amino acids can be classified as N-alkyl amino acids and can also be classified according to the characteristics of their side chains.

[0403] In some embodiments, the unnatural amino acids incorporated into the peptides include one or more of the following: 1) a keto functional group (such as that found in para- or meta-acetyl-phenylalanine), which can react specifically with hydrazine, hydroxylamine, and their derivatives (Addition of the keto functional group to the genetic code of Escherichia coli. Wang L, Zhang Z, Brock A, Schultz P G. Proc Natl Acad Sci USA. January 7, 2003; 100(1):56-61; Bioorg Med Chem Lett. October 15, 2006; 16(20):5356-9. Genetic introduction of a diketone-containing amino acid into proteins. Zeng H, Xie J, Schultz P G), 2) an azide (such as that found in para-azidophenylalanine), which can react with an alkyne via copper-catalyzed "click chemistry" or strain-promoted (3+2) cycloaddition reaction to form the corresponding triazole (Addition of p-azido-L-phenylalanine to the genetic code of Escherichia coli. Chin J W, Santoro S W, Martin A B, King D S, Wang L, Schultz P G. J Am Chem Soc. August 7, 2002; 124(31):9026-7; Adding amino acids with novel reactivity to the genetic code of Saccharomyces cerevisiae. Deiters A, Cropp T A, Mukherji M, Chin J W, Anderson J C, Schultz P G. J Am Chem Soc.Journal of the American Chemical Society, October 1, 2003; 125(39): 11782-3), or azides that can react with arylphosphines via the Staudinger ligation reaction (Selective Staudinger modification of proteins containing p-azidophenylalanine. Tsao M L, Tian F, Schultz P G. Chembiochem. December 2005; 6(12): 2147-9), to form the corresponding amides, 3) alkynes, which can react with azides to form the corresponding triazoles (In vivo incorporation of an alkyne into proteins in Escherichia coli. Deiters A, Schultz P G. Bioorg Med Chem Lett. March 1, 2005; 15(5): 1521-4), and 4) boronic acids (boronates), which can react specifically with compounds containing more than one appropriately spaced hydroxyl group or undergo palladium-mediated coupling with halogenated compounds (Angew Chem Int Ed Engl. 2008; 47(43): 8220-3. A genetically encoded boronate-containing amino acid., Brustad E, Bushey M L, Lee J W, Groff D, Liu W, Schultz P G).

[0404] The peptides of the present disclosure include their various derivatives. Examples of derivatives include those having an amide, ester, or carboxyl group as their C-terminus and / or N-terminus. Additional examples of peptide derivatives include those obtained by modification such as phosphorylation, methylation, acetylation, adenylylation, ADP-ribosylation, or glycosylation, as well as fusion proteins obtained by fusion with another peptide or protein. These derivatives can be prepared by those skilled in the art in known ways or methods based thereon.

[0405] In some embodiments, the peptides described herein include basic amino acids. Examples of basic amino acids include arginine, lysine, citrulline, ornithine, creatine, histidine, diaminobutyric acid, and diaminopropionic acid.

[0406] In some embodiments, peptides are provided herein that have 90% or greater sequence identity to any of the sequences disclosed herein. In some embodiments, the sequence identity is at least 95% or 99%.

[0407] In some embodiments, the peptide is bicyclic or polycyclic. In some embodiments, the conjugates described herein comprise a bicyclic peptide. Exemplary bicyclic peptides include the bicyclic targeting peptides of BT5528, BT1718, and BT8009. Exemplary bicyclic peptides are described in US20180200378, US10441663, US 8680022B2, US20180280525, and US20200215199, each of which is incorporated herein by reference in its entirety. In some cases, when the peptide is cyclized, protease resistance is improved, metabolic stability is improved, and the restriction on conformational changes is increased, resulting in increased rigidity, and membrane permeability and affinity for the target protein are improved. In some embodiments, the peptides disclosed herein have a cyclic structure in which a chloroacetylated amino acid is bound to a cysteine residue present in the peptide. In one aspect, the peptide has a cyclic structure in which the N-terminal amino acid is bound to a cysteine residue present in the peptide. In some embodiments, the peptide has a cyclic structure in which the N-terminal amino acid is bound to the thirteenth cysteine residue present in the peptide. In some embodiments, the peptide has a cyclic structure in which a chloroacetylated N-terminal amino acid is bound to the cysteine residue at position 12 present in the peptide. "Chloroacetylated" can be replaced with "haloacetylated" using another halogen. In addition, "acetylated" can be "acylated" using an acyl group other than an acetyl group.

[0408] In some embodiments, the peptide is a lasso peptide. Lasso peptides can be synthetic or naturally produced by bacteria, and they have a unique threaded lasso fold that provides a 3D functional array for engaging biological targets. This lasso structure can confer beneficial properties such as affinity, stability, and potent bioactivity. Appropriate lasso structures can be designed through algorithms. Exemplary lasso peptides are provided in: Hegemann, J.D., et al., Lasso Peptides: An Intriguing Class of Bacterial Natural Products, Acc. Chem. Res., 2015, 48, 1909-1919; Tietz, J.I., et al., A new genome-mining tool redefines the lasso peptide biosynthetic landscape, Nature Chem Bio, 2017, 13, 470-478; DiCaprio, A.J., et al., Enzymatic Reconstitution and Biosynthetic Investigation of the Lasso Peptide Fusilassin, J. Am. Chem. Soc., 2019, 141, 290-297; Al Toma, R.S., et al., Site-Directed and Global Incorporation of Orthogonal and Isostructural Noncanonical Amino Acids into the Ribosomal Lasso Peptide Capistruin, ChemBioChem, 2015, 16, 503–509.

[0409] Further exemplary peptides include BMS-753493, somatostatin, octreotide, octreotate, lanreotide, pasireotide, JR-11, L-779,976, BIM-23120, satoreotide, depreotide, 18F-KYNDRLPLYISNP (SEQ ID NO:274), CaIX-P1, and FAP-2286.

[0410] The peptides of the present disclosure include salts thereof. As salts of the peptides, salts formed with physiologically acceptable bases or acids are used. Examples include addition salts with inorganic acids (such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, or phosphoric acid), organic acids (such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, carboxylic acids, succinic acid, citric acid, benzoic acid, or acetic acid), inorganic bases (such as ammonium hydroxide, alkali or alkaline earth metal hydroxides, carbonates, or bicarbonates), and amino acids.

[0411] In addition, linkers can also be added to (cyclic) peptides. Examples of linkers include the aforementioned amino acid linkers (peptide linkers), chemical linkers, fatty acid linkers, nucleic acid linkers, sugar linkers, etc., or it can be a complex, such as a chemical linker, peptide linker, etc. Examples of chemical linkers include PEG (polyethylene glycol) linkers. For example, a PEG linker can contain 1 to 24 ethylene glycol units. In addition, the linker can be a fatty acid linker containing a divalent chemical moiety derived from a fatty acid. The linker includes at least one amino acid, and for example, a glycine-rich peptide can be used, such as a peptide having the sequence [Gly-Gly-Gly-Gly-Ser]n (in the formula, n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO:275)), such as the peptide according to U.S. Patent No. 7,271,149 (incorporated herein by reference), or the serine-rich peptide linker according to U.S. Patent No. 5,525,491 (incorporated herein by reference). In a non-limiting manner, there are some cases where the physical properties (such as solubility) of the peptide can be changed by adding a linker. In one aspect, the amino acid linker includes the amino acid sequence according to any one of SEQ ID NOs: 1 to 171.

[0412] The linker can be added at any position. For example, it can bind to Cys located on the C-terminal side, or can bind to an amino acid contained in the cyclic peptide. In some cases, it binds to Cys or its variant located on the C-terminal side. In this case, the linker is added to the -COOH on the Cys residue. It may be possible to add one to several amino acids to the C-terminal of such Cys residues and then add the linker to its end; for example, in a cyclic peptide, Gly is added to the C-terminal of Cys, and then the -COOH of this Gly is bound to a linker such as a PEG linker or an amino acid linker. In other cases, the linker is added to the side chain of an amino acid (preferably Lys) within the cyclic peptide. In this case, for example, the linker is added to the side chain of Lys at X5, X8 or X10. EphA2-binding peptide and peptide having EphA2 antagonistic activity

[0413] EPH receptor A2 (ephrin type-A receptor 2) is a human protein encoded by the EPHA2 gene. EphA2 may be upregulated in a variety of cancers and is generally associated with disease progression, metastasis and poor prognosis in solid tumors such as breast solid tumors, lung solid tumors, gastric solid tumors, pancreatic solid tumors, prostate solid tumors, liver solid tumors and glioblastoma.

[0414] Eph receptor tyrosine kinases (Ephs) belong to a large group of receptor tyrosine kinases (RTKs) that phosphorylate proteins on tyrosine residues. Ephs and their membrane-bound ephrin ligands (ephrins) can control cell positioning and tissue organization. Functional and biochemical Eph responses may occur at higher ligand oligomerization states.

[0415] In addition to other patterned functions, various Ephs and ephrins have been shown to play a role in blood vessel development. Knockout of EphB4 and ephrin B2 can lead to the loss of the ability to remodel capillary beds into blood vessels and cause embryonic lethality. Persistent expression of some Eph receptors and ephrins has also been observed in newly formed adult microvessels (Brantley-Sieders et al. (2004) Curr Pharm Des [Current Pharmaceutical Design] 10, 3431-42). The reappearance of dysregulation of some ephrins and their receptors in adults may contribute to tumor invasion, metastasis and neovascularization. In addition, some Eph family members may be overexpressed in tumor cells from a variety of human tumors (Booth et al. (2002) Nat Med [Nature Medicine] 8, 1360-1).

[0416] In some embodiments, the peptides of the present technology bind to EphA2. In some of these embodiments, the peptides have EphA2 antagonist activity. In some cases, the peptides bind to human EphA2 (hEphA2) and have hEphA2 antagonist activity.

[0417] As used herein, the term "EphA2" refers to any form of EphA2 and variants thereof that retain at least some EphA2 activity. Unless explicitly described as human EphA2 (hEphA2), EphA2 includes all native sequences of EphA2 in mammals (such as, for example, human, dog, cat, horse, and cow). One example of EphA2 is hEphA2 (Gene ID: 1969), which is human EphA2 and is a protein having the amino acid sequence (SEQ ID NO: 276, isoform 1, P29317-1).

[0418] MELQAARACFALLWGCALAAAAAAQGKEVVLLDFAAAGGELGWLTHPYGKGWDLMQNIMNDMPIYMYSVCNVMSGDQDNWLRTNWVYRGEAERIFIELKFTVRDCNSFPGGASSCKETFNLYYAESDLDYGTNFQKRLFTKIDTIAPDEITVSSDFEARHVKLNVEERSVGPLTRKGFYLAFQDIGACVALLSVRVYYKKCPELLQGLAHFPETIAGSDAPSLATVAGTCVDHAVVPPGGEEPRMHCAVDGEWLVPIGQCLCQAGYEKVEDACQACSPGFFKFEASESPCLECPEHTLPSPEGATSCECEEGFFRAPQDPASMPCTRPPSAPHYLTAVGMGAKVELRWTPPQDSGGREDIVYSVTCEQCWPESGECGPCEASVRYSEPPHGLTRTSVTVSDLEPHMNYTFTVEARNGVSGLVTSRSFRTASVSINQTEPPKVRLEGRSTTSLSVSWSIPPPQQSRVWKYEVTYRKKGDSNSYNVRRTEGFSVTLDDLAPDTTYLVQVQALTQEGQGAGSKVHEFQTLSPEGSGNLAVIGGVAVGVVLLLVLAGVGFFIHRRRKNQRARQSPEDVYFSKSEQLKPLKTYVDPHTYEDPNQAVLKFTTEIHPSCVTRQKVIGAGEFGEVYKGMLKTSSGKKEVPVAIKTLKAGYTEKQRVDFLGEAGIMGQFSHHNIIRLEGVISKYKPMMIITEYMENGALDKFLREKDGEFSVLQLVGMLRGIAAGMKYLANMNYVHRDLAARNILVNSNLVCKVSDFGLSRVLEDDPEATYTTSGGKIPIRWTAPEAISYRKFTSASDVWSFGIVMWEVMTYGERPYWELSNHEVMKAINDGFRLPTPMDCPSAIYQLMMQCWQQERARRPKFADIVSILDKLIRAPDSLKTLADFDPRVSIRLPSTSGSEGVPFRTVSEWLESIKMQQYTEHFMAAGYTAIEKVVQMTNDDIKRIGVRLPGHQKRIAYSLLGLKDQVNTVGIPI(SEQ ID NO:276).

[0419] Another isoform of human EphA2 may have the sequence according to SEQ ID NO: 277 (isoform 2, P29317-2) as follows:

[0420] MELQAARACFALLWGCALAAAAAAQGKEVVLLDFAAAGGELGWLTHPYGKGWDLMQNIMNDMPIYMYSVCNVMSGDQDNWLRTNWVYRGEAERIFIELKFTVRDCNSFPGGASSCKETFNLYYAESDLDYGTNFQKRLFTKIDTIAPDEITVSSDFEARHVKLNVEERSVGPLTRKGFYLAFQDIGACVALLSVRVYYKKCPELLQGLAHFPETIAGSDAPSLATVAGTCVDHAVVPPGGEEPRMHCAVDGEWLVPIGQCLCQAGYEKVEDACQACSPGFFKFEASESPCLECPEHTLPSPEGATSCECEEGFFRAPQDPASMPCTRPPSAPHYLTAVGMGAKVELRWTPPQDSGGREDIVYSVTCEQCWPESGECGPCEASVRYSEPPHGLTRTSVTVSDLEPHMNYTFTVEARNGVSGLVTSRSFRTASVSINQTEPPKVRLEGRSTTSLSVSWSIPPPQQSRVWKYEVTYRKKVTPRGAGLALAGPTAGDRLVT (SEQ ID NO: 277)

[0421] As used herein, the expression "has an affinity for EphA2" or "binds to EphA2" means having the activity of binding to EphA2. The binding site of the peptide of the present invention on EphA2 is not limited, and the peptide can bind anywhere on the EphA2 protein. The binding to EphA2 can be measured by any known method for measuring intermolecular binding. In a non-limiting manner, for example, this can be carried out by competitive binding assays (such as surface plasmon resonance (SPR) assays, scattering assays and / or radioimmunoassays (RIA), enzyme immunoassays (EIA) as well as sandwich assays and competitive assays) and in any known suitable manner (including different variants of the given examples known in the art).

[0422] In some embodiments, the peptides of the present invention competitively bind hEphA2 at one or more amino acid residues selected from: Asp53, Met55, Asn57, Met59, Met66, Thr101, Arg103, Phe156, Glu157, Arg159, Val161, Val189, and Ala190. In some embodiments, the peptide competitively binds human EphA2 at one or more amino acid residues selected from: Asp53, Phe156, and Glu157. In some embodiments, the peptide competitively binds human EphA2 at Asp53, Glu157, or both.

[0423] In one aspect, as determined by the Kd in surface plasmon resonance (SPR) assays, the binding affinity of the peptides of the present technology is at most 100 nM. In some embodiments, the Kd of the peptides of the present technology is 100 nM or lower, 50 nM or lower, 30 nM or lower, 20 nM or lower, 10 nM or lower, 5 nM or lower, 4 nM or lower, 3 nM or lower, 2 nM or lower, 1 nM or lower, 0.9 nM or lower, 0.5 nM or lower, 0.4 nM or lower, 0.3 nM or lower, 0.2 nM or lower, 0.1 nM or lower, 0.09 nM or lower, 0.08 nM or lower, 0.07 nM or lower, 0.06 nM or lower, 0.05 nM or lower, 0.04 nM or lower, 0.03 nM or lower, 0.02 nM or lower, 0.01 nM or lower.

[0424] In some embodiments, as determined by the Kd in surface plasmon resonance (SPR) assays, the peptides described herein have a binding affinity for human EphA2 of at most 1, 5, 10, 50, 100, 200, 500, 1000, 5000, or 10,000 nM. In some embodiments, as determined by the Kd in surface plasmon resonance (SPR) assays, the peptides described herein have a binding affinity for human EphA2 of at most 100 nM. In some embodiments, as determined by the Kd in surface plasmon resonance (SPR) assays, the peptides described herein have a binding affinity for human EphA2 of at most 1 nM. In some embodiments, as determined by the Kd in surface plasmon resonance (SPR) assays, the peptides described herein have a binding affinity for human EphA2 of at most 2 nM. In some embodiments, as determined by the Kd in surface plasmon resonance (SPR) assays, the peptides described herein have a binding affinity for human EphA2 of at most 5 nM. In some embodiments, as determined by the Kd in surface plasmon resonance (SPR) assays, the peptides described herein have a binding affinity for human EphA2 of at most 10 nM.

[0425] In some embodiments, as determined by Kd in surface plasmon resonance (SPR) assays, the conjugates described herein have a binding affinity for human EphA2 of at most 1, 5, 10, 50, 100, 200, 500, 1000, 5000, or 10,000 nM. In some embodiments, as determined by Kd in surface plasmon resonance (SPR) assays, the conjugates described herein have a binding affinity for human EphA2 of at most 100 nM. In some embodiments, as determined by Kd in surface plasmon resonance (SPR) assays, the conjugates described herein have a binding affinity for human EphA2 of at most 1 nM. In some embodiments, as determined by Kd in surface plasmon resonance (SPR) assays, the conjugates described herein have a binding affinity for human EphA2 of at most 2 nM. In some embodiments, as determined by Kd in surface plasmon resonance (SPR) assays, the conjugates described herein have a binding affinity for human EphA2 of at most 5 nM. In some embodiments, as determined by Kd in surface plasmon resonance (SPR) assays, the conjugates described herein have a binding affinity for human EphA2 of at most 10 nM.

[0426] In one aspect, as determined by Kd in surface plasmon resonance (SPR) assays, the binding affinity of the peptides or conjugates of the present disclosure is at most 100 nM. In some embodiments, the Kd of the peptides or conjugates of the present disclosure is 100 nM or lower, 50 nM or lower, 30 nM or lower, 20 nM or lower, 10 nM or lower, 5 nM or lower, 4 nM or lower, 3 nM or lower, 2 nM or lower, 1 nM or lower, 0.9 nM or lower, 0.5 nM or lower, 0.4 nM or lower, 0.3 nM or lower, 0.2 nM or lower, 0.1 nM or lower, 0.09 nM or lower, 0.08 nM or lower, 0.07 nM or lower, 0.06 nM or lower, 0.05 n M or lower, 0.04 n M or lower, 0.03 n M or lower, 0.02 n M or lower, 0.01 n M or lower. Unnatural amino acid

[0427] In certain embodiments, the peptides and conjugates described herein comprise one or more unnatural amino acids, which are not any of the 20 standard amino acids found in proteins. Representative unnatural amino acids that can be incorporated into the peptides and conjugates described herein are provided in the table below. Table 3. Structures of exemplary unnatural amino acids that can be incorporated into the peptides / conjugates described herein Linker & Peptide-Linker

[0428] Prior to further linking such peptide-linker intermediates with payload molecules to form the conjugates described herein, the peptides described herein can be linked with one or more linkers. Accordingly, the conjugates described herein can include one or more linkers. In some embodiments, the linker covalently links the peptide to the payload molecule in the conjugate. In some other embodiments, the peptide is directly attached to the payload molecule without a linker. In some embodiments, the present disclosure describes linkers that act as spacers.

[0429] The linker can include a plurality of spacer atoms (on a linear chain, excluding side groups or substituents) between the payload molecule and the binding peptide described herein, thereby creating a distance between the payload molecule and the binding peptide. In some embodiments, the linker includes 10-100 spacer atoms between the payload molecule and the binding peptide. In some embodiments, the linker includes 2-60 spacer atoms between the payload molecule and the binding peptide. In some embodiments, the linker includes 2 to 20, 2 to 50, 5 to 15, 5 to 25, 10 to 40, 30 to 60, or 10 to 20 spacer atoms between the payload molecule and the binding peptide. In some embodiments, the linker includes 3 to 30 spacer atoms between the payload molecule and the binding peptide. In some embodiments, the linker includes 5 to 25 spacer atoms between the payload molecule and the binding peptide. In some embodiments, the linker includes 6 to 18 spacer atoms between the payload molecule and the binding peptide. In some embodiments, the linker includes 10 to 20 spacer atoms between the payload molecule and the binding peptide. The spacer atoms can include one or more carbons, and optionally one or more heteroatoms such as O and N. In some embodiments, the spacer atoms include 2 to 20, 2 to 50, 5 to 15, 5 to 25, 10 to 40, 30 to 60, or 10 to 20 carbons. In some embodiments, the spacer atoms include 0, 1, 2, 3, 4, 5, or 6 nitrogens. In some embodiments, the spacer atoms include 0, 1, 2, 3, 4, 5, 6, 7, or 8 oxygens. In some embodiments, the spacer atoms include 1 to 6 nitrogens and 0 to 4 oxygens.

[0430] The linker may comprise one or more amino acid residues. In some embodiments, the linker comprises 1 to 3, 1 to 5, 1 to 10, 5 to 10, or 5 to 20 amino acid residues. In some embodiments, the linker comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid residues. In some embodiments, the linker comprises 1 to 5 amino acid residues. For example, the linker may comprise one or more lysine (K) residues, such as the K, KK, or KKK sequences. In some embodiments, the linker comprises lysine or a derivative thereof. In some embodiments, the linker comprises lysine. In some embodiments, one or more amino acids of the linker are non-natural amino acids. In some embodiments, the linker comprises lysine residues, alanine residues, or both. In certain embodiments, the linker comprises one or more amino acids selected from lysine residues, alanine residues, or phenylalanine residues. In some embodiments, the linker comprises lysine residues. In some embodiments, the linker comprises alanine residues.

[0431] The linker described herein can be attached to the N-terminus of a peptide, the C-terminus of a peptide, or a non-terminal amino acid of a peptide, or it can be attached to the peptide by a combination of the above. In some embodiments, the linker is attached to the peptide through its N-terminus. In some embodiments, the linker is attached to the peptide through a cysteine residue at the C-terminus. In some embodiments, the linker is attached to the peptide through a cysteine residue at the N-terminus. In some embodiments, the linker is attached to the peptide through its C-terminus. In some embodiments, the linker is attached to the peptide through a non-terminal amino acid. The linker can be bonded to the peptide, the payload molecule, or both, for example, through a chemically reactive group. Exemplary chemical reaction groups include, but are not limited to, free amino, imino, hydroxyl, thiol, or carboxyl groups (e.g., the N-terminus or C-terminus, the ε-amino group of one or more lysine residues, the free carboxylic acid group of one or more glutamic acid or aspartic acid residues, or the thiol group of one or more cysteine residues). The site at which the linker binds to the peptide can be a natural or non-natural amino acid of the peptide, and / or it can be introduced into the peptide, for example, by DNA recombination techniques (e.g., by introducing a cysteine or protease cleavage site into the amino acid sequence) or by protein biochemistry (e.g., reduction, pH adjustment, or proteolysis). Exemplary methods for attaching the linker include carbodiimide reactions, reactions using bifunctional agents (e.g., dialdehydes or iminoesters), Schiff base reactions, Suzuki-Miyaura cross-coupling reactions, isothiocyanates as coupling agents, and click chemistry.

[0432] The linker can have a defined length to connect the payload molecule and the peptide while allowing an appropriate distance therebetween. In some embodiments, the linker has a length of 1 to 100 atoms, 1 to 60 atoms, 1 to 30 atoms, 1 to 15 atoms, 1 to 10 atoms, 1 to 5 atoms, or 2 to 20 atoms. In some embodiments, the linker has a length of 1 to 10 atoms.

[0433] The linker may comprise flexible and / or rigid regions. Exemplary flexible linker regions include those comprising Gly and Ser residues (“GS” linker), glycine residues, alkylene chains, PEG chains, etc. Exemplary rigid linker regions include those comprising α-helix forming sequences (e.g., EAAAK (SEQ ID NO:278)), proline-rich sequences, and regions rich in double and / or triple bonds.

[0434] The linker may be cleavable, for example, under physiological conditions (e.g., intracellular conditions), such that cleavage of the linker releases the payload molecule in the intracellular environment. The linker may be, for example, a peptidyl linker that is cleaved by intracellular peptidases or proteases (including, but not limited to, lysosomal or endosomal proteases). In some embodiments, the peptidyl linker is at least two amino acids long or at least three amino acids long. Cleaving agents may include cathepsin B and D and plasmin. In other embodiments, the linker is non-cleavable. In some embodiments, the linker is pH-sensitive, i.e., sensitive to hydrolysis at certain pH values. For example, a pH-sensitive linker may be hydrolyzed under acidic conditions. For example, the linker may be an acid-labile linker (e.g., hydrazone, semicarbazone, thiosemicarbazone, cis-aconitate, orthoester, acetal, ketal, etc.) that is hydrolyzable in lysosomes. Such linkers may be relatively stable at neutral pH conditions (such as those in blood), but unstable at pH values below 5.5 or 5.0 (approximate pH of lysosomes). In some embodiments, the hydrolyzable linker is a thioether linker.

[0435] In some embodiments, the linker comprises an amino acid sequence, e.g., a combination of an amino acid sequence with flexible and / or rigid regions, as exemplified in Table 6B, shown in the “Linker” column. For example, PDC_EphA2-00010011-C003 includes a linker comprising amino acid residues, bA-dk. In another example, PDC_EphA2-00001417-C004 includes a linker comprising a combination of amino acid residues and PEG, kA-dk-(PEG8c-PEG2c).

[0436] In some embodiments, the linker may comprise an amino acid sequence, or a combination of an amino acid sequence with flexible and / or rigid regions, such as those provided in Table 13 (see “Linker / Payload” column). For example, in Table 13, biotin, sulfo Cys5 is shown as the payload. PDC_EphA2-00010011-C003 includes a linker, bA-dk, comprising amino acid residues.

[0437] In some embodiments, the linker comprises one or more of the following: substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In some embodiments, the linker comprises substituted or unsubstituted C1-C 30 alkylene. In some embodiments, the linker comprises polyethylene glycol, such as (-CH2-CH2-O-) 1-10 . In some embodiments, the linker comprises a structure selected from the following: and a structure derived from any one thereof.

[0438] In some embodiments, the linker comprises click chemistry residues. In some embodiments, the linker is attached to the peptide, to the payload molecule, or to both via click chemistry, thereby forming click chemistry residues. For example, the peptide may comprise an azide group (at the N-terminus or C-terminus or at a non-terminal amino acid) that reacts with the alkyne moiety of the linker. As another example, the peptide may comprise an alkyne group (at the N-terminus or C-terminus or at a non-terminal amino acid) that reacts with the azide of the linker. The payload molecule and the linker may be attached similarly. In some embodiments, the linker comprises an azide moiety, an alkyne moiety, or both. In some embodiments, the linker comprises a triazole. In some embodiments, the click chemistry residue is (DBCO-azide residue), In some embodiments, the click chemistry residue is a DIBO-azide residue, a BARAC-azide residue, a DBCO-azide residue, a DIFO-azide residue, a COMBO-azide residue, a BCN-azide residue, or a DIMAC-azide residue. In some embodiments, the linker comprises residues for nitrone cycloaddition. In some embodiments, the linker comprises residues for tetrazine ligation. In some embodiments, the linker comprises residues for norbornane ligation. Exemplary groups of click chemistry residues are shown in the following: Hein et al., “Click Chemistry, A Powerful Tool for Pharmaceutical Sciences,” Pharmaceutical Research, Vol. 25, pp. 2216–2230 (2008); Thirumurugan et al., “Click Chemistry for Drug Development and Diverse Chemical–Biology Applications,” Chem. Rev. 2013, 113, 7, 4905–4979; US20160107999A1; US10266502B2; and US20190204330A1, each of which is incorporated by reference in its entirety.

[0439] In some embodiments, the linker described herein comprises two or more motifs. In some embodiments, one or more of the motifs are connected via click chemistry such that they can be clicked into / out of the linker. Each motif in the linker can have an independent function. For example, the linker can comprise a motif that serves to modulate the plasma half-life and / or a motif that serves as a spacer between the peptide and the payload molecule.

[0440] In some embodiments, the linker has the following structure where each L is independently -O-, –NR L -, –N(R L )2 + -, -OP(=O)(OR L )O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR L -, -NR L C(=O)-, -OC(=O)NRL -, -NR L C(=O)O-, -NR L C(=O)NR L -, -NR L C(=S)NR L -, -CR L =N-, -N=CR L , -NR L S(=O)2-, -S(=O)2NR L -, -C(=O)NR L S(=O)2-, -S(=O)2NR L C(=O)-, substituted or unsubstituted C3-C 15 cycloalkyl, substituted or unsubstituted C1-C 12 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C 30 alkylene, substituted or unsubstituted C2-C 30 alkenylene, substituted or unsubstituted C2-C 30 alkynylene, substituted or unsubstituted C1-C 30 heteroalkylene, -(C1-C 30 alkylene)-O-, -O-(C1-C 30 alkylene)-, -(C1-C 30 alkylene)-NR L -, -NR L -(C1-C 30 alkylene)-, -(C1-C 30 alkylene)-N(R L )2 + -, -N(R L )2 + -(C1-C 30 alkylene)-, or a click chemistry residue; and each R L is independently hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and n is from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20). In some embodiments, the linker has The structure, where each L is independently -O-, –NR L -, –N(R L )2 + -, -OP(=O)(OR L )O-, -S-, -S(=O)-, -S(=O)2-, -CH=CH-, =CH-, -C≡C-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR L -, -NR L C(=O)-, -OC(=O)NR L -, -NR L C(=O)O-, -NR L C(=O)NR L -, -NR L S(=O)2-, -S(=O)2NR L -, -C(=O)NR L S(=O)2- or -S(=O)2NR L C(=O)-.

[0441] In some embodiments, the linker having formula (II-1) has the structure of formula (II-1a), where L 1 and L 3 each independently is -O-, –NR L (-), –N(R L )2-, -OP(=O)(OR L )O-, -S-, -S(=O)-, -S(=O)2-, -CH=CH-, =CH-, -C≡C-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR L (-), -NR L C(=O)-, -OC(=O)NR L (-), -NR L C(=O)O-, -NR L C(=O)NR L (-), -NR L S(=O)2-, -S(=O)2NR L (-), -C(=O)NR L S(=O)2- or -S(=O)2NR L C(=O)-; and L 2 is absent, substituted or unsubstituted C1-C30 an alkylene group, or a substituted or unsubstituted C1-C 30 heteroalkylene group.

[0442] In some embodiments, the linker comprises a structure of formula (II-1b), wherein L 1 and L 5 each independently is -O-, –NR L -, –N(R L )2-, -OP(=O)(OR L )O-, -S-, -S(=O)-, -S(=O)2-, -CH=CH-, =CH-, -C≡C-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR L -, -NR L C(=O)-, -OC(=O)NR L -, -NR L C(=O)O-, -NR L C(=O)NR L -, -NR L S(=O)2-, -S(=O)2NR L -, -C(=O)NR L S(=O)2-, -S(=O)2NR L C(=O)-, a substituted or unsubstituted 5- to 6-membered cycloalkyl group, or a substituted or unsubstituted 5- to 6-membered heteroalkyl group; and L 2 , L 3 and L 4 each independently is absent, a substituted or unsubstituted 5- to 6-membered cycloalkyl group, a substituted or unsubstituted 5- to 6-membered heteroalkyl group, a substituted or unsubstituted C1-C 30 alkylene group, or a substituted or unsubstituted C1-C 30 heteroalkylene group.

[0443] In some embodiments, L 1 is -NH-.

[0444] In some embodiments, L 2 is absent. In some embodiments, L 2 is a substituted or unsubstituted C1-C 30 alkylene group, or a substituted or unsubstituted C1-C 30 heteroalkylene group. In some embodiments, L 2 is a substituted or unsubstituted C1-C 30Alkylene. In some embodiments, L 2 is a substituted or unsubstituted C1-C 30 heteroalkylene. In some embodiments, L 2 is a substituted or unsubstituted C1-C 18 alkylene, or a substituted or unsubstituted C1-C 18 heteroalkylene. In some embodiments, L 2 is optionally substituted. In some embodiments, L 2 is optionally substituted by one or more substituents selected from: -OH, -SH, oxo, amino, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, -C(=O)OR L , -OC(=O)R L , -OC(=O)OR L , -C(=O)N(R L )2, -NR L C(=O)R L , -OC(=O)N(R L )2 and -NR L C(=O)OR L . In some embodiments, L 2 is a C1-C 30 heteroalkylene, which is optionally substituted by one or more substituents selected from: -OH, -SH, oxo, amino, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl and C1-C6 aminoalkyl. In some embodiments, L2 is optionally substituted by a C1-C6 alkyl, which is further optionally substituted by one or more substituents selected from: -OH, -SH, oxo, amino, C6-C 10 aryl, 6- to 10-membered heteroaryl, -C(=O)OR L , -OC(=O)R L , -OC(=O)OR L , -C(=O)N(R L )2, -NR L C(=O)R L , -OC(=O)N(R L )2 and -NR L C(=O)OR L .

[0445] In some embodiments, L 3 is -NH-. In some embodiments, L 3 is absent.

[0446] In some embodiments, L 4does not exist. In some embodiments, L 4 is a substituted or unsubstituted 5- to 6-membered cycloalkyl, a substituted or unsubstituted 5- to 6-membered heterocycloalkyl, a substituted or unsubstituted C1-C 30 alkylene, or a substituted or unsubstituted C1-C 30 heteroalkylene.

[0447] In some embodiments, L 5 is -NH-. In some embodiments, L 5 does not exist.

[0448] In some embodiments of formula (II-1b), L 1 is -O-, -N(methyl)-, -NH-, or -C(=O)-; L 5 is -O-, -N(methyl)-, -NH-, or -C(=O)-; L 2 , L 3 and L 4 are each independently non-existent, a substituted or unsubstituted 5- to 6-membered cycloalkyl, a substituted or unsubstituted 5- to 6-membered heterocycloalkyl, a substituted or unsubstituted C1-C 12 alkylene, or a substituted or unsubstituted C1-C 30 heteroalkylene, wherein L 1 is linked to the payload molecule, and L 5 is linked to the EphA2 binding peptide.

[0449] In some embodiments of formula (II-1b), L 2 is an unsubstituted C1-C 12 alkylene, and L 3 and L 4 do not exist.

[0450] In some embodiments, the linker comprises a substituted or unsubstituted C1-C 30 alkylene, C1-C 12 alkylene, C1-C8 alkylene, C1-C6 alkylene or C2-C6 alkylene. In some embodiments, the linker comprises C2-C6 alkylene. In some embodiments, the linker comprises C4-C6 alkylene.

[0451] In some embodiments, each of L 1 is independently -O-, –NR L -, –N(R L )2-, -OP(=O)(OR L )O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL -, -NR L C(=O)-, -OC(=O)NR L -, -NR L C(=O)O-, -NR L C(=O)NR L -, -NR L C(=S)NR L -, -CR L =N-, -N=CR L , -NR L S(=O)2-, -S(=O)2NR L -, -C(=O)NR L S(=O)2-, -S(=O)2NR L C(=O)-, substituted or unsubstituted C3-C 15 cycloalkyl, substituted or unsubstituted C1-C 12 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C 30 alkylene, substituted or unsubstituted C2-C 30 alkenylene, substituted or unsubstituted C2-C 30 alkynylene, or substituted or unsubstituted C1-C 30 heteroalkylene. In some embodiments, L 1 is -O-, –NR L -, -OP(=O)(OR L )O-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR L -, -NR L C(=O)-, -OC(=O)NR L -, -NR L C(=O)O-, -NR L C(=O)NR L -, -NR L C(=S)NR L -, -NR L S(=O)2-, -S(=O)2NR L -, -C(=O)NR L S(=O)2- or -S(=O)2NR L C(=O)-. In some embodiments, L 1 is -O-, -NH-, -S(=O)-, -S(=O)2- or -C(=O)-. In some embodiments, L 1is -C(=O)NH- or -NHC(=O)-. In some embodiments, L 1 is a substituted or unsubstituted C3-C 15 cycloalkyl, or a substituted or unsubstituted C1-C 12 heterocycloalkyl. In some embodiments, L 1 is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. In some embodiments, L 1 is a substituted or unsubstituted C1-C 30 alkylene. In some embodiments, L 1 is a substituted or unsubstituted C2-C 30 alkenylene. In some embodiments, L 1 is a substituted or unsubstituted C1-C 30 heteroalkylene. In some embodiments, L 1 is a substituted or unsubstituted C5-C 25 heteroalkylene. In some embodiments, L 1 is a substituted or unsubstituted C5-C 12 heteroalkylene.

[0452] In some embodiments, each of the L 2 is independently O-, –NR L -, –N(R L )2-, -OP(=O)(OR L )O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR L -, -NR L C(=O)-, -OC(=O)NR L -, -NR L C(=O)O-, -NR L C(=O)NR L -, -NR L C(=S)NR L -, -CR L =N-, -N=CR L -, -NR L S(=O)2-, -S(=O)2NR L -, -C(=O)NR L S(=O)2-, -S(=O)2NR L C(=O)-, a substituted or unsubstituted C3-C 15 cycloalkyl, a substituted or unsubstituted C1-C 12Heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C 30 alkylene, substituted or unsubstituted C2-C 30 alkenylene, substituted or unsubstituted C2-C 30 alkynylene, or substituted or unsubstituted C1-C 30 heteroalkylene. In some embodiments, L 2 is -O-, –NR L -, -OP(=O)(OR L )O-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR L (=O)-, -NR L C(=O)-, -OC(=O)NR L (=O)-, -NR L C(=O)O-, -NR L C(=O)NR L (=O)-, -NR L C(=S)NR L (=O)-, -NR L S(=O)2-, -S(=O)2NR L (=O)-, -C(=O)NR L S(=O)2- or -S(=O)2NR L (=O)-. In some embodiments, L 2 is -O-, -NH-, -S(=O)-, -S(=O)2- or -C(=O)-. In some embodiments, L 2 is -C(=O)NH- or -NHC(=O)-. In some embodiments, L 2 is substituted or unsubstituted C3-C 15 cycloalkyl, or substituted or unsubstituted C1-C 12 heterocycloalkyl. In some embodiments, L 2 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, L 2 is substituted or unsubstituted C1-C 30 alkylene. In some embodiments, L 2 is substituted or unsubstituted C2-C 30 alkenylene. In some embodiments, L 2 is substituted or unsubstituted C1-C 30 heteroalkylene. In some embodiments, L 2 is substituted or unsubstituted C5-C 25 heteroalkylene. In some embodiments, L2 is a substituted or unsubstituted C5-C 12 alkylene.

[0453] In some embodiments, each of the L 3 is independently -O-, –NR L -, –N(R L )2-, -OP(=O)(OR L )O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR L -, -NR L C(=O)-, -OC(=O)NR L -, -NR L C(=O)O-, -NR L C(=O)NR L -, -NR L C(=S)NR L -, -CR L =N-, -N=CR L , -NR L S(=O)2-, -S(=O)2NR L -, -C(=O)NR L S(=O)2-, -S(=O)2NR L C(=O)-, a substituted or unsubstituted C3-C 15 cycloalkyl, a substituted or unsubstituted C1-C 12 heterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted C1-C 30 alkylene, a substituted or unsubstituted C2-C 30 alkenylene, a substituted or unsubstituted C2-C 30 alkynylene, or a substituted or unsubstituted C1-C 30 alkylene. In some embodiments, L 3 is -O-, –NR L -, -OP(=O)(OR L )O-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR L -, -NR L C(=O)-, -OC(=O)NR L -, -NR L C(=O)O-, -NR L C(=O)NRL -, -NR L C(=S)NR L -, -NR L S(=O)2-, -S(=O)2NR L -, -C(=O)NR L S(=O)2- or -S(=O)2NR L C(=O)-. In some embodiments, L 3 is -O-, -NH-, -S(=O)-, -S(=O)2-, or -C(=O)-. In some embodiments, L 3 is -C(=O)NH- or -NHC(=O)-. In some embodiments, L 3 is a substituted or unsubstituted C3-C 15 cycloalkyl, or a substituted or unsubstituted C1-C 12 heterocycloalkyl. In some embodiments, L 3 is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. In some embodiments, L 3 is a substituted or unsubstituted C1-C 30 alkylene. In some embodiments, L 3 is a substituted or unsubstituted C2-C 30 alkenylene. In some embodiments, L 3 is a substituted or unsubstituted C1-C 30 heteroalkylene. In some embodiments, L 3 is a substituted or unsubstituted C5-C 25 heteroalkylene. In some embodiments, L 3 is a substituted or unsubstituted C5-C ...

Claims

1. A (cyclic) peptide that has an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide comprises an amino acid sequence that includes one or more (e.g., 1 - 6) deletions, substitutions, and / or additions of the following amino acids: the amino acid sequence of SEQ ID NO:1 da-MeF-N-L-Hgl-MeF-W1Me-V-W1Me-T-E-C (SEQ ID NO:1) or a pharmaceutically acceptable salt thereof, wherein the (cyclic) peptide consists of 10 to 12 amino acid residues.

2. The (cyclic) peptide according to claim 1, wherein 1 - 5 amino acids selected from the group consisting of: N at position 3, L at position 4, MeF at position 6, T at position 10, and E at position 11 of SEQ ID NO:1 are deleted, optionally without any additional addition and / or substitution.

3. The (cyclic) peptide according to claim 1 or 2, wherein one or more (e.g., 1, 2, 3, 4, or 5) amino acids are added.

4. The (cyclic) peptide according to any one of claims 1 to 3, wherein one or more amino acid residues selected from the following are substituted: MeF at position 2, MeF at position 6, V at position 8, and E at position 11.

5. The (cyclic) peptide according to any one of claims 1 to 4, wherein the peptide comprises an amino acid sequence that has 2 or fewer amino acids deleted from amino acid SEQ ID NO:1, optionally without any additional addition and / or substitution.

6. The (cyclic) peptide according to claim 5, wherein 1 - 2 amino acids selected from the group consisting of: T at position 10 and E at position 11 of SEQ ID NO:1 are deleted, optionally without any additional addition and / or substitution.

7. A (cyclic) peptide that has an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide comprises the amino acid sequence of formula (I) or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is an amino acid; X2 is an amino acid containing an aromatic ring, its N-methylated amino acid, or a variant thereof; X3 is a hydrophilic amino acid (e.g., N, Q, Cit, K, or a variant thereof), glycine (G), alanine (A), or a variant thereof (e.g., da, 2-aminoisobutyric acid (Aib)); X4 is a hydrophobic amino acid (e.g., leucine (L)), a hydrophilic amino acid (e.g., citrulline (Cit)), or a variant thereof; X5 is a hydrophilic amino acid or a variant thereof; X6 is a hydrophilic amino acid, an amino acid containing an aromatic ring, or its N-methylated amino acid; X7 is an amino acid containing an aromatic ring (e.g., W, F, or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, an N-methylated amino acid, or a variant thereof; X9 is an amino acid containing an aromatic ring (e.g., W or a variant thereof); X10 is absent or is a hydrophilic amino acid (e.g., threonine (T) or a variant thereof); X11 is absent or is a hydrophilic amino acid; and X12 is cysteine (C) or a variant thereof.

8. The (cyclic) peptide according to claim 7, wherein X3 is a hydrophilic amino acid.

9. The (cyclic) peptide according to claim 8, wherein X3 is an amino acid comprising a charged side chain (e.g., K or a variant thereof), an amino acid comprising a polar uncharged side chain (e.g., Q, Cit, N, or a variant thereof), or G, A or a variant thereof.

10. The (cyclic) peptide according to any one of claims 7-9, wherein X4 is a hydrophobic amino acid.

11. The (cyclic) peptide according to claim 10, wherein X4 is an amino acid comprising a hydrophobic side chain (e.g., L), an amino acid comprising a polar uncharged side chain (e.g., Cit or a variant thereof).

12. The (cyclic) peptide according to any one of claims 7-11, wherein X5 is a hydrophilic amino acid.

13. The (cyclic) peptide according to claim 12, wherein X5 is an amino acid comprising a charged side chain (e.g., E, Hgl, D, or a variant thereof) or an amino acid comprising a polar uncharged side chain (e.g., Q, Cit, Hgn, N, or a variant thereof).

14. The (cyclic) peptide according to any one of claims 7-13, wherein X6 is a hydrophilic amino acid.

15. The (cyclic) peptide according to claim 14, wherein X6 is an amino acid comprising a charged side chain (e.g., E, Hgl, D, or a variant thereof) or an amino acid comprising a polar uncharged side chain (e.g., Q, Cit, Hgn, N, or a variant thereof).

16. The (cyclic) peptide according to any one of claims 7-15, wherein X11 is a hydrophilic amino acid.

17. The (cyclic) peptide according to claim 16, wherein X11 is an amino acid comprising a charged side chain (e.g., E, Hgl, D, R, hArg, K or a variant thereof) or an amino acid comprising a polar uncharged side chain (e.g., Q, Cit, Hgn, N, or a variant thereof).

18. The (cyclic) peptide according to any one of claims 1-17, wherein the peptide has the amino acid sequence of formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) X1 is an amino acid; X2 is F, or a variant thereof, wherein the unsubstituted phenyl ring of F is replaced with the following: (i) A phenyl ring substituted with 1 or 2 substituents each independently selected from the following: -OH, -CN, -C 1-3 alkyl (e.g., -CH3), or (ii) A 6-membered heteroaryl ring optionally substituted with 1 or 2 substituents each independently selected from the following: -OH, -CN, -C 1-3 alkyl (e.g., -CH3), wherein the F or its structural variant is optionally N-methylated; X3 is a hydrophilic amino acid (e.g., N, Q, Cit, K or a variant thereof), G, Aib, Hgn, Ala, or a variant thereof (e.g., da); X4 is a hydrophobic amino acid (e.g., an amino acid having 4 or more carbon atoms in a side chain comprising a straight-chain, branched-chain or cyclic carbon chain), and wherein X4 is optionally N-methylated (e.g., Cit or a variant thereof); X5 is an amino acid (e.g., a hydrophilic amino acid; Dab, Dap, R, E or a variant thereof; or an amino acid with a functional side chain (e.g., non-glycine)); X6 is its N-methylated amino acid; X7 is W, Y, or a variant thereof (e.g., an amino acid having a 6-membered aryl or heteroaryl, or a 9- or 10-membered bicyclic aryl or heteroaryl linked to the α-carbon through carbon (e.g., a methylene group), wherein the 6-, 9-, and 10-membered heteroaryls have one heteroatom (e.g., N), and wherein the 6-, 9-, and 10-membered aryl or heteroaryl is optionally substituted with 1 or 2 substituents independently selected from: –CH3, -ethyl, -Cl, and -F); X8 is an amino acid having –H on the α-amino group; X9 is W or Y or a variant thereof; (e.g., W or a variant thereof); X10 is absent, or a polar amino acid (e.g., T or a variant thereof); X11 is absent, or an amino acid (e.g., a hydrophilic amino acid; Dab, Dap, R, E or a variant thereof; or an amino acid with a functional side chain (e.g., non-glycine)); and X12 is C or a variant thereof.

19. The (cyclic) peptide according to any one of claims 1 to 18, wherein the peptide has the amino acid sequence of formula (Ia), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X12 Formula (Ia) wherein, X1 is an amino acid (e.g., a D-amino acid); X2 is an amino acid containing an aromatic ring, its N-methylated amino acid, or a variant thereof; X3 is a hydrophilic amino acid (e.g., N, Q, Cit, K or a variant thereof), G, A, or a variant thereof (e.g., da, Aib); X4 is a hydrophobic amino acid, or a hydrophilic amino acid (e.g., Cit or a variant thereof); X5 is a hydrophilic amino acid (e.g., Dab, Dap, R, E, Q, D, K) or a variant thereof; X6 is a hydrophilic amino acid, an amino acid containing an aromatic ring (e.g., W, or F, or a variant thereof) or its N-methylated amino acid; X7 is an amino acid containing an aromatic ring (e.g., W, F, or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, or an N-methylated amino acid; X9 is an amino acid containing an aromatic ring (e.g., W, F or a variant thereof); and X12 is C or a variant thereof.

20. The (cyclic) peptide according to any one of claims 1 to 18, wherein the peptide has the amino acid sequence according to formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is an amino acid (e.g., a D-amino acid); X2 is an amino acid containing an aromatic ring, its N-methylated amino acid, or a variant thereof; X3 is a hydrophilic amino acid (e.g., N, Q, Cit, K or a variant thereof), G, A, or a variant thereof (e.g., da, Aib); X4 is a hydrophobic amino acid, or a hydrophilic amino acid (e.g., Cit or a variant thereof); X5 is a hydrophilic amino acid (e.g., Dab, Dap, R, E, Q, D, K) or a variant thereof; X6 is a hydrophilic amino acid, an amino acid containing an aromatic ring (e.g., W, or F, or a variant thereof) or its N-methylated amino acid; X7 is an amino acid containing an aromatic ring (e.g., W, F, or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, or an N-methylated amino acid; X9 is an amino acid containing an aromatic ring (e.g., W, F or a variant thereof); X10 is a hydrophilic amino acid (e.g., T, S, N, Q, K, Cit, or a variant thereof); X11 is a hydrophilic amino acid; and X12 is C or a variant thereof.

21. The (cyclic) peptide according to any one of claims 1 to 20, wherein X1 is an amino acid (e.g., a D-amino acid); X2 is F, Y, W, a variant thereof, or an N-methylated amino acid thereof; X3 is N, Q, Cit, G, Aib, K, A, or a variant thereof; X4 is G, A, Cit, or a variant thereof (e.g., G substituted with a linear or branched C 1-5 alkyl, G substituted with a C 3-7 cycloalkyl, or A substituted with a C 3-7 cycloalkyl); X5 is a hydrophilic L-amino acid, wherein the L-amino acid contains a functional group selected from the following: -NH2, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2, and -NHC(O)CH3; X6 is a hydrophilic amino acid, F, Y, W, an N-methylated amino acid thereof, or a variant thereof, wherein the hydrophilic amino acid contains a functional group selected from the following: -C(O)OH, -C(O)NH2, and -NHC(O)CH3; X7 is F, W, or a variant thereof; X8 is G substituted by one or two linear or branched C 1-5 alkyl, G substituted by C 3-7 cycloalkyl, A substituted by C 3-7 cycloalkyl, or a hydrophilic L-amino acid, where the hydrophilic L-amino acid contains -NH2, one or more -OH, -C(O)OH, -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2 or -NHC(O)CH3; or the hydrophilic amino acid contains zwitterions; X9 is F, W, or a variant thereof; X10 is absent, Q, S, K, Cit, N, T, or a variant thereof (e.g., Q, S, K, Cit, N or T optionally substituted with a straight-chain or branched C 1-5 alkyl group) or an L-amino acid containing -NHC(NH)NH2, -NHC(O)NH2, -C(O)NH2 or -NHC(O)CH3; X11 is absent, E, Q, R, Cit, K, D, or N, or a variant thereof; and X12 is C or a variant thereof.

22. The (cyclic) peptide according to any one of claims 1 to 21, wherein the peptide has an amino acid sequence according to formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is da, df3CON, dkCOpipzaa, dahp, dDab-NH2-Ph3-SO2F, dDap-NH2-Ph3-SO2F, dDap-NH2-Ph4-SO2F, dCit, Aib, G, norvaline, norleucine, d4PyCON, or dhAla; X2 is MeF, Me3Py, MeF3CON, MeF3F, Me4Py, or MeY(Me); X3 is absent, N, Q, Cit, G, Aib, Hgn, hCit, norCit, LysAc, OrnAc, Ala, or da; X4 is L, Cbg, Chg, Cba, Cha, Ahx, Dahp, Cit, I, V, norleucine, or norvaline; X5 is Hgl, Hgn, Dab, Dap, DabAc, DapAc, R, hArg, E, or D; X6 is absent, MeF, MeE, Me3Py, Me4Py, MeF4F, MeF4F, MeF4C, or MeY; X7 is W1Me, W1Me7Cl, W1Me7N, W, F, 7-AzaTrp, W7Me, W1Et, W1Me7Br, W1Me7OMe, or W1Me6O7Cl; X8 is V, KCOpipzaa, N, Cit, Q-reduced glucosamine, hCit, K, KAc, Aib, Alb, DapAc, OrnAc, A, T, alT, norleucine, norvaline, Hgl, E, Hgn, Q, I or L; X9 is W1Me, W1Me7Cl, W1Me7N, F23dMe, W1Et, W7Me, W, F or 7-AzaTrp; X10 is absent, T, Q, S, Hgn, α-methylserine, hSer, hThr, N, OrnAc, LysAc, Cit or hCit; X11 is absent, E, Hgn, R, hArg, Cit, hCit, Hgl, Orn, D, N, Q, DapAc, OrnAc, DabAc, norCit; and X12 is C, hCys, CdMe, C3RMe, C3SMe, selenocysteine, dc or penicillamine.

23. The (cyclic) peptide according to any one of claims 18-22, wherein X7 is W1Me or a variant thereof; and X9 is W1Me or a variant thereof.

24. The (cyclic) peptide according to any one of claims 18-23, wherein X7 is W1Me, W1MeCl, W1MeBr, Nal1, Nal2, W1Et, 3Bzf, 3Bzt, F23dC, W1Me7N or F23dMe; X8 is V, KCOpipzaa, N, Cit, hCit, KAc, DapAc, OrnAc, A, T, alT, Aib, Alb, Q-reduced glucosamine, Hgl, Q, E, Hgn or K; and X8 is V, KCOpipzaa, N, Cit, hCit, KAc, DapAc, OrnAc, A, T, alT, Aib, Alb, Q-reduced glucosamine, Hgl, Q, E, Hgn or K; and X9 is W1Me, Nal1, W1Et, Nal21N, 3Bzf, 3Bzt, Nal18N, F23dMe or F23dC.

25. The (cyclic) peptide according to any one of claims 1 to 17, wherein the peptide comprises an amino acid sequence according to formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is any amino acid, X2 is an amino acid having an aromatic ring or a variant thereof, X3 is N, X4 is a hydrophobic amino acid or a variant thereof; X5 is a hydrophilic amino acid or a variant thereof; X6 is a hydrophilic amino acid or an amino acid having an aromatic ring; X7 is W or a variant thereof; X8 is V or a hydrophilic amino acid or a variant thereof, X9 is W or a variant thereof; X10 is T or a variant thereof; X11 is a hydrophilic amino acid; X12 is C or a variant thereof (e.g., C).

26. The (cyclic) peptide according to any one of claims 1 to 17, wherein the peptide has an amino acid sequence according to formula (Ia), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X12 Formula (Ia) wherein X1 is any amino acid; X2 is an amino acid having an aromatic ring or a variant thereof; X3 is N or a variant thereof; X4 is a hydrophobic amino acid or a variant thereof, X5 is a hydrophilic amino acid or a variant thereof; X6 is a hydrophilic amino acid or an amino acid having an aromatic ring; X7 is W or a variant thereof; X8 is a hydrophilic amino acid or a variant thereof, X9 is W or a variant thereof; and X12 is C or a variant thereof.

27. A (cyclic) peptide that has an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide consists of: The sequence of formula (I), X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) or a pharmaceutically acceptable salt thereof, wherein each of X1, X2, X3, X4, X5, X6 and X8 is independently an amino acid; X7 is W1Me or a variant thereof; X9 is W1Me or a variant thereof; each of X10 and X11 is independently absent or is an amino acid; and X12 is cysteine (C) or a variant thereof; and, optionally, a linker that links the peptide to a payload molecule.

28. The (cyclic) peptide according to any one of claims 7-27, wherein the variant of the amino acid is selected from amino acids having one, two or three substituents based on the amino acid, and wherein these substituents are independently selected from halogen, -CN, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, oxo, -OH, -CO2H, -CO2-C1-C3 alkyl, -C(=O)NH2, -C(=O)NH(C1-C3 alkyl), -C(=O)N(C1-C3 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C3 alkyl), -S(=O)2N(C1-C3 alkyl)2, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C6-C 10 aryl, C3-C6 cycloalkyl, 6-10 membered heteroalkyl and 6-10 membered heteroaryl.

29. The (cyclic) peptide according to claim 28, wherein the variant is selected from amino acids having one or two substituents based on the amino acid, and wherein the substituents are independently selected from halogen, -CN, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, oxo, -OH, -CO2H, -CO2-C1-C3 alkyl, -C(=O)NH2, -C(=O)NH(C1-C3 alkyl), -C(=O)N(C1-C3 alkyl)2 and C1-C6 alkyl.

30. The (cyclic) peptide according to any one of claims 7-29, wherein the variant is selected from amino acids having similar hydrophilicity or hydrophobicity compared to the reference amino acid.

31. The (cyclic) peptide according to any one of claims 7-29, wherein the variant is selected from amino acids having the same functional groups as the reference amino acid, and wherein the variant has a different side chain length compared to the reference amino acid.

32. The (cyclic) peptide according to any one of claims 7-31, wherein the variant has a molecular weight that varies by no more than 14, 28, 30, 45 or 60 g / mol compared to the reference amino acid.

33. A (cyclic) peptide that has an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide has the amino acid sequence of formula (I), X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein X1 is any D- or L-amino acid; X2 has the structure of, where ring A2 is phenyl or a 6-membered heteroaryl (e.g., heteroaryl having 1 or 2 Ns); R X2 Each independently is halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-SH、SF5、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d 、C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally and independently substituted by one or more R XA Substituted; kx2 is 0, 1, 2 or 3; mx2 is 0, 1, 2, 3 or 4; R NX2 is H, a C1-C6 alkyl or a C1-C6 haloalkyl; *X1 represents the attachment point to X1; and, *X3 represents the attachment point to X3; X3 has structure, where kx3 is 0, 1, 2 or 3; NX3 is H, a C1-C6 alkyl or a C1-C6 haloalkyl; R X3 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; *X2 represents the attachment point to X2; and, *X4 represents the attachment point to X4; X4 is a hydrophobic amino acid (e.g., an amino acid having 4 or more carbon atoms in a side chain comprising a straight-chain, branched-chain or cyclic carbon chain), and wherein X4 is optionally N-alkylated by a C 1-3 alkyl group; X5 is a hydrophilic L-amino acid, such as an amino acid having a structure, wherein: R NX5 is H, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl or heteroalkyl is optionally and independently substituted by one or more R XA substituents; R X5 is -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, SF5, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b , -NR c C(=O)NR d , -NR b C(=NR b )NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl or heteroalkyl is optionally and independently substituted by one or more R XA substituted; The condition is R NX5 and R X5 at least one of which contains a moiety selected from the following: -OH, -NH2, and -NH- (e.g., -NH-C(=NH)-NH2, -CO-NH2, -NH2, -COOH, -C(OH)-C 0-6 alkyl, -NH-CO-C 1-6 alkyl); *X4 represents the attachment point to X4; and, *X6 represents the attachment point to X6; X6 is (e.g., N, F), where R NX6 is H, a C1-C6 alkyl group or a C1-C6 haloalkyl group; R X6 is -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, SF5, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b , -NR c C(=O)NR d , -NR b C(=NR b )NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally and independently substituted by one or more R XA substituted; *X5 represents the attachment point to X5; and, *X7 represents the attachment point to X7; X7 has structure, where R NX7 is H, a C1-C6 alkyl group or a C1-C6 haloalkyl group; Ring A7 is aryl or heteroaryl; R X7 Each independently is halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, SF5, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2-halogen, -S(=O)2NR c R d , -NR c R d , -NR b , -NR c R d , -NR b , -NR a , -NR b , -NR b , -NR b , -NR a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally and independently substituted by one or more R XA substituted; kx7 is 0, 1, 2, or 3; mx7 is 0, 1, 2, 3, 4, or 5; *X6 represents the attachment point to X6; and, *X8 represents the attachment point to X8; X8 is an L - amino acid with - H on the α - amino group; X9 has the structure of, where R NX9 is H, a C1-C6 alkyl or a C1-C6 haloalkyl; Ring A9 is aryl or heteroaryl; R X9 each independently is halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-SH、SF5、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d 、C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally and independently substituted by one or more R XA substituted; kx9 is 0, 1, 2, or 3; mx9 is 0, 1, 2, 3, 4, or 5; *X8 represents the attachment point to X8; and, *XC represents the attachment point to (i) X10 or (i) X12 when both X10 and X11 are absent; X10 is absent or is an L - amino acid; X11 is absent or is an L - amino acid; provided that when X10 is absent, then X11 is also absent; and X12 is an L - amino acid with a reactive thiol group, such as Cys and Cys variants; Each R a is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl) or C1-C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more Rs; Each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Each R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl) or C1-C6 alkyl(heteroaryl); where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R; or R c and R d together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more R; and Each R and R XA is independently halogen, -CN, -OH, -OC1-C6 alkyl, SF5, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NR b C(=NR b )NR c R d , -NHC(=O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; Optionally, the peptide is linked to a payload molecule through a linker.

34. The (cyclic) peptide according to claim 33, wherein ring A7 is a 6 - membered aryl or heteroaryl, or a 9 - or 10 - membered bicyclic aryl or heteroaryl, and the 6 -, 9 -, or 10 - membered heteroaryl has one heteroatom selected from N, O, and S.

35. The (cyclic) peptide according to claim 33 or 34, wherein R NX7 is H.

36. The (cyclic) peptide according to any one of claims 33 to 35, wherein each R X7 is independently selected from -CH3, -ethyl, -Cl and -F, and mx7 is 0, 1 or 2.

37. The (cyclic) peptide according to claim 33, wherein X7 is W1Me, Nal1, Nal2, W1Et, Nal21N, 3Bzf, 3Bzt, Nal15N, Nal14N, Nal24N, Nal28N, F23dMe, F23dC, W1Me7N, or W1Me7Cl.

38. The (cyclic) peptide according to claim 37, wherein X7 is W1Me, F23dMe, or W1Me7Cl.

39. The (cyclic) peptide according to any one of claims 33 to 38, wherein X9 is each R X9 independently selected from -OH, CN, NH2, C1-C3 alkyl, -Cl, -F, -Br, -CONH2 and -SO2F.

40. The (cyclic) peptide according to any one of claims 33 to 39, wherein is 41. The (cyclic) peptide according to any one of claims 33 to 40, wherein R X9 is independently selected from halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -SH, a , -SR a , -S(=O)R a , -S(=O)2R c R d , -NR c R d , -NR b C(=O)R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl.

42. The (cyclic) peptide according to any one of claims 33 to 38, wherein X9 is W1Me, W, Nal1, W1Et, Nal21N, 3Bzf, 3Bzt, Nal14N, Nal18N, F23dMe, F23dC, or W1Et.

43. The (cyclic) peptide according to claim 42, wherein X9 is W1Me or F23dMe.

44. The (cyclic) peptide according to any one of claims 33 to 43, wherein ring A2 is a 6 - membered heteroaryl containing 1 or 2 Ns.

45. The (cyclic) peptide according to any one of claims 33 to 44, wherein R X5 is C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -C 0-6 alkylene-NH-C(=NH)-NH2, -C 0-6 alkylene-CO-NH2, -C 0-6 alkylene-COOH or -NH-CO-C 1-6 alkyl.

46. The (cyclic) peptide according to any one of claims 27 - 33, wherein X7 is W1Me, W1MeCl, W1MeBr, Nal1, Nal2, W1Et, 3Bzf, 3Bzt, F23dC, W1Me7N, or F23dMe; X8 is V, KCOpipzaa, Hse, N, Cit, hCit, KAc, DapAc, OrnAc, T, alT, Aib, Alb, Q - glucosamine, Hgl, E, Hgn, MeF, 3Py6NH2, W1Me, A, Q, or K; and X9 is W1Me, Nal1, W1Et, Nal21N, 3Bzf, 3Bzt, Nal18N, F23dMe, or F23dC.

47. The (cyclic) peptide according to claim 24 or 46, wherein X7 is W1Me; X8 is V; and X9 is W1Me.

48. The (cyclic) peptide according to any one of claims 1-47, wherein the peptide or a pharmaceutically acceptable salt thereof has a cyclic structure in which the first amino acid (or X1) is covalently linked to the last amino acid (or X12).

49. The (cyclic) peptide according to any one of claims 1-48, wherein the peptide or a pharmaceutically acceptable salt thereof has a cyclic structure having an amino acid and a cysteine residue or a variant thereof at the first residue X1, and wherein the amino acid at X1 forms a covalent bond with the cysteine residue or a variant thereof.

50. The (cyclic) peptide according to any one of claims 1-49, wherein the peptide has a monocyclic structure.

51. The (cyclic) peptide according to claim 50, wherein the amino acid X1 forms a covalent bond with cysteine or a variant thereof.

52. The (cyclic) peptide according to any one of claims 1-51, wherein the peptide has a structure of formula (I-1), wherein R 1 selected from the group consisting of: NH2 and OH; R 2 selected from the group consisting of: H or C 1-3 alkyl; R 3 selected from the group consisting of: H or C 1-3 alkyl; wherein X1 to X11 have the definitions described in formula (I).

53. The (cyclic) peptide of claim 52, or a pharmaceutically acceptable salt thereof, wherein the peptide having the formula (I-1) has a structure of formula (I-2).

54. The (cyclic) peptide according to any one of claims 1-53, wherein the peptide or a salt thereof comprises an amino acid sequence that is at least 95% identical to a sequence selected from SEQ ID NO: 1-171, or a sequence having up to 1, 2, 3, 4, or 5 substitutions by conservative variants compared to any one of the sequences selected from SEQ ID NO: 1-171.

55. The (cyclic) peptide according to any one of claims 1-54, wherein the peptide or a salt thereof consists of an amino acid sequence selected from SEQ ID NO: 1-171.

56. The (cyclic) peptide of claim 55, wherein the peptide consists of an amino acid sequence selected from SEQ ID NO: 1-122, 159-163, and 165-171, and the peptide has a cyclic structure having a cysteine residue or a variant thereof at the 12th residue, and wherein the amino acid at X1 (e.g., a chloroacetylated amino acid) forms a covalent bond with the cysteine residue or a variant thereof at the 12th residue (e.g., by reacting the chloroacetyl group in the X1 amino acid with the cysteine residue or a variant thereof).

57. The (cyclic) peptide of claim 55, wherein the peptide consists of an amino acid sequence selected from SEQ ID NO: 123-149 and 164, and the peptide has a cyclic structure having a cysteine residue or a variant thereof at the 10th residue, and wherein the amino acid at X1 (e.g., a chloroacetylated amino acid) forms a covalent bond with the cysteine residue or a variant thereof at the 10th residue.

58. (Cyclic) peptide according to any one of claims 1-57, wherein the peptide has a binding affinity for human EphA2 of at most 100 nM as determined by K in surface plasmon resonance (SPR) analysis d as determined.

59. The (cyclic) peptide according to claim 58, wherein the peptide has a binding affinity for human EphA2 of at most 1 nM as determined by K in surface plasmon resonance (SPR) analysis d as determined.

60. The (cyclic) peptide according to any one of claims 1-59, wherein the peptide binds to the ligand-binding domain (LBD) of EphA2.

61. The (cyclic) peptide according to any one of claims 1-60, wherein the peptide interacts with human EphA2 at one or more amino acid residues selected from the following: Asp53, Met55, Asn57, Met59, Met66, Thr101, Arg103, Phe156, Glu157, Arg159, Val161, Val189, and Ala190.

62. The (cyclic) peptide according to any one of claims 1-61, wherein the peptide interacts with human EphA2 at the Asp53 and Glu157 sites.

63. The (cyclic) peptide according to any one of claims 1-62, wherein the peptide has a plasma half-life (T 1 / 2 ) of at least 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 minutes as determined in vitro in human plasma at 37 °C.

64. The (cyclic) peptide according to claim 63, wherein the peptide has a plasma half-life (T 1 / 2 ) of at least 250 minutes as determined in vitro in human plasma at 37 °C.

65. The (cyclic) peptide according to any one of claims 1-64, which is covalently linked to a linker that connects the peptide to a payload molecule.

66. The (cyclic) peptide according to claim 65, wherein the linker is attached to the peptide via a non-terminal amino acid residue of the peptide.

67. The (cyclic) peptide according to claim 66, wherein the linker is attached to the 5th amino acid residue or X5.

68. The (cyclic) peptide according to claim 66, wherein the linker is attached to the 8th amino acid residue or X8.

69. The (cyclic) peptide according to claim 66, wherein the linker is attached to the 11th amino acid residue or X11.

70. The (cyclic) peptide according to any one of claims 65-69, wherein the linker is attached to a lysine of the peptide.

71. The (cyclic) peptide according to any one of claims 65-70, wherein the linker is attached to the peptide via the N-terminus of the peptide.

72. The (cyclic) peptide according to any one of claims 65-70, wherein the linker is attached to the peptide via the C-terminus of the peptide.

73. The (cyclic) peptide according to any one of claims 65-72, wherein the linker is a bond.

74. The (cyclic) peptide according to any one of claims 65-72, wherein the linker contains 3 to 30 spacer atoms between the payload molecule and the peptide.

75. The (cyclic) peptide according to any one of claims 65-72, wherein the linker contains 6 to 18 spacer atoms between the payload molecule and the peptide.

76. The (cyclic) peptide according to claim 74 or 75, wherein the spacer atoms contain 1 to 6 nitrogens and 0 to 4 oxygens.

77. The (cyclic) peptide according to any one of claims 65-72 and 74-76, wherein the linker contains one or more amino acid residues.

78. The (cyclic) peptide according to claim 77, wherein the linker contains one or more amino acids selected from lysine residues, alanine residues, or phenylalanine residues.

79. The (cyclic) peptide according to any one of claims 65-72 and 74-78, wherein the linker contains one or more structures selected from AEEA, AEEP, AEEEP, and AEEEEP.

80. The (cyclic) peptide according to any one of claims 65-72, wherein the linker has the structure of formula (II-1) wherein each L is independently -O-, -NR L -, -N(R L )2-, -OP(=O)(OR L )O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR L -, -NR L C(=O)-, -OC(=O)NR L -, -NR L C(=O)O-, -NR L C(=O)NR L -, -NR L C(=S)NR L -, -CR L =N-, -N=CR L , -NR L S(=O)2-, -S(=O)2NR L -, -C(=O)NR L S(=O)2-, -S(=O)2NR L C(=O)-, substituted or unsubstituted C3-C 15 cycloalkyl, substituted or unsubstituted C1-C 12 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C 30 alkylene, substituted or unsubstituted C2-C 30 alkenylene, substituted or unsubstituted C2-C 30 alkynylene, substituted or unsubstituted C1-C 30 heteroalkylene, -(C1-C 30 alkylene)-O-, -O-(C1-C 30 alkylene)-, -(C1-C 30 alkylene)-NR L -, -NR L -(C1-C 30 alkylene)-, -(C1-C 30 alkylene)-N(R L )2- or -N(R L )2-(C1-C 30 alkylene)-; and Each R L is independently hydrogen, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C1-C4 heteroalkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C5 alkynyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C2-C7 heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group; and n is from 1 to 20.

81. The (cyclic) peptide according to claim 80, wherein the linker contains the structure of formula (II-1a), wherein L 1 and L 3 each independently is -O-, –NR L -, –N(R L )2-, -OP(=O)(OR L )O-, -S-, -S(=O)-, -S(=O)2-, -CH=CH-, =CH-, -C≡C-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR L (-), -NR L C(=O)-, -OC(=O)NR L (-), -NR L C(=O)O-, -NR L C(=O)NR L (-), -NR L S(=O)2-, -S(=O)2NR L (-), -C(=O)NR L S(=O)2- or -S(=O)2NR L C(=O)-; and L 2 is an unsubstituted or substituted C1-C 30 alkylene, or a substituted or unsubstituted C1-C 30 heteroalkylene.

82. The (cyclic) peptide according to claim 81, wherein L 1 is -NH-.

83. The (cyclic) peptide according to claim 81 or 82, wherein L 2 is a substituted or unsubstituted C1-C 30 alkylene, or a substituted or unsubstituted C1-C 30 heteroalkylene.

84. The (cyclic) peptide according to claim 81 or 82, wherein L 2 is a substituted or unsubstituted C1-C 18 alkylene, or a substituted or unsubstituted C1-C 18 heteroalkylene.

85. The (cyclic) peptide according to any one of claims 81 to 84, wherein L 2 is optionally substituted with one or more substituents selected from the following: -OH, -SH, oxo, amino, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, -C(=O)OR L , -OC(=O)R L , -OC(=O)OR L , -C(=O)N(R L )2, -NR L C(=O)R L , -OC(=O)N(R L )2 and -NR L C(=O)OR L ; and the C1-C6 alkyl is further optionally substituted with one or more substituents selected from the following: -OH, -SH, oxo, amino, C6-C 10 aryl, 6- to 10-membered heteroaryl, -C(=O)OR L , -OC(=O)R L , -OC(=O)OR L , -C(=O)N(R L )2, -NR L C(=O)R L , -OC(=O)N(R L )2 and -NR L C(=O)OR L .

86. The (cyclic) peptide according to any one of claims 81 to 85, wherein L 3 is -NH-.

87. The (cyclic) peptide according to claim 81, wherein the linker has structure 88. The (cyclic) peptide according to claim 81, wherein the linker has the following structure:

89. (Cyclic) peptides according to any one of claims 1-88, wherein the peptide is a peptide having formula (I), and wherein when the peptide binds to human EphA2, amino acid residue X7 is located less than from Phe156 of human EphA2.

90. The (cyclic) peptide according to claim 89, wherein the amino acid residue X7 is located less than from the Phe156.

91. The (cyclic) peptide according to claim 89, wherein the amino acid residue X7 is located less than from the Phe156.

92. A (cyclic) peptide according to any one of claims 1-91, wherein the peptide is a peptide having formula (I), and wherein when the peptide binds to human EphA2, amino acid residue X9 is located less than from Phe156 of human EphA2.

93. The (cyclic) peptide according to claim 92, wherein the amino acid residue X9 is located at a position less than from the Phe156.

94. The (cyclic) peptide according to claim 93, wherein the amino acid residue X9 is located at a distance less than from the Phe156.

95. A (cyclic) peptide as claimed in any one of claims 1-94, wherein the peptide is a peptide having formula (I), and wherein when the peptide binds to human EphA2, amino acid residue X8 is located less than from Phe156 of human EphA2.

96. The (cyclic) peptide according to any one of claims 89 to 95, wherein the human EphA2 comprises the sequence of SEQ ID NO: 276 or SEQ ID NO:

277.

97. A (cyclic) peptide that has an affinity for ephrin type-A receptor 2 (EphA2) and competes with a peptide having an amino acid sequence with one or several amino acid deletions, substitutions, or additions selected from the following for binding to human EphA2: the amino acids of SEQ ID NO: 1 da-MeF-N-L-Hgl-MeF-W1Me-V-W1Me-T-E-C (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof.

98. A (cyclic) peptide that has an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide competes with a peptide having the structure of formula (I) or a pharmaceutically acceptable salt thereof for binding to human EphA2, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) wherein, X1 is an amino acid; X2 is an amino acid containing an aromatic ring, its N-methylated amino acid, or a variant thereof; X3 is a hydrophilic amino acid (such as N, Q, Cit, K or a variant thereof), glycine (G), alanine (A) or a variant thereof (such as, da, 2-aminoisobutyric acid (Aib)); X4 is a hydrophobic amino acid (such as, leucine (L)), a hydrophilic amino acid (such as, citrulline (Cit)) or a variant thereof; X5 is a hydrophilic amino acid or a variant thereof; X6 is a hydrophilic amino acid, an amino acid containing an aromatic ring, or its N-methylated amino acid; X7 is an amino acid containing an aromatic ring (such as, W, F, or a variant thereof); X8 is a hydrophobic amino acid, a hydrophilic amino acid, an N-methylated amino acid, or a variant thereof; X9 is an amino acid containing an aromatic ring (such as, W or a variant thereof); X10 is absent or is a hydrophilic amino acid (such as, threonine (T) or a variant thereof); X11 is absent or is a hydrophilic amino acid; and X12 is cysteine (C) or a variant thereof.

99. A (cyclic) peptide that has an affinity for ephrin type-A receptor 2 (EphA2), wherein the peptide consists of: The sequence of formula (I), X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) or a pharmaceutically acceptable salt thereof, wherein each of X1, X2, X3, X4, X5, X6, and X8 is independently an amino acid; X7 is W1Me or a variant thereof; X9 is W1Me or a variant thereof; each of X10 and X11 is independently absent or is an amino acid; and X12 is cysteine (C) or a variant thereof; and, wherein the peptide is optionally linked to a payload molecule through a linker.

100. A (cyclic) peptide as claimed in any one of claims 97 to 99, wherein the peptide competes for binding to human EphA2 at one or more amino acid residues selected from the group consisting of Asp53, Met55, Asn57, Met59, Met66, Thr101, Arg103, Phe156, Glu157, Arg159, Val161, Val189 and Ala190.

101. A (cyclic) peptide as claimed in claim 100, wherein the peptide competes for binding to human EphA2 at one or more amino acid residues selected from the group consisting of Asp53, Phe156 and Glu157.

102. A (cyclic) peptide as claimed in any one of claims 97 to 101, wherein the human EphA2 comprises the sequence of SEQ ID NO:276 or SEQ ID NO:

277.

103. A pharmaceutical composition comprising a peptide or a salt thereof as claimed in any one of claims 1 - 102, and a pharmaceutically acceptable excipient or carrier.

104. A conjugate comprising a peptide or a salt thereof as claimed in any one of the foregoing claims, and a substance, wherein the substance is selected from the group consisting of nucleotides, small molecules, medium-sized molecules (e.g., having a M.W. of about 1,000 - 2,500 Da), large-sized molecules (e.g., having a M.W. > 2,500 Da), polymeric compounds, proteins, peptides, tags, biological fragments, carriers including pharmaceutical compounds, or combinations thereof.

105. A method for treating a disease or disorder characterized by overexpression of EphA2, the method comprising administering to a subject a peptide or a salt thereof as claimed in any one of claims 1 - 102, a conjugate as claimed in claim 103 or a pharmaceutical composition as claimed in claim 104.

106. The method as claimed in claim 105, wherein the disease or disorder is cancer.

107. The method as claimed in claim 106, wherein the cancer is selected from the group consisting of glioblastoma, prostate cancer, lung cancer, breast cancer, gastric cancer, ovarian cancer, bladder cancer, colon cancer, esophageal cancer, multiple myeloma and fibrosarcoma.

108. The method as claimed in claim 106, wherein the cancer is non-small cell lung cancer (NSCLC).

109. The method as claimed in claim 106, wherein the cancer is triple-negative breast cancer.

110. A kit, test agent or composition for determining the expression level of EphA2 in a sample, wherein the kit, test agent or composition comprises a peptide or a salt thereof as claimed in any one of claims 1 - 102, a conjugate as claimed in claim 103 or a pharmaceutical composition as claimed in claim 104.

111. The kit, test agent or composition as claimed in claim 110, which is suitable for use in a method for diagnosing a disease or disorder characterized by overexpression or reduced expression of EphA2.

112. The kit, test agent or composition according to claim 110 or 111, wherein the sample is from a subject suffering from a disease or disorder characterized by overexpression or reduced expression of EphA2.

113. Use of the peptide or a salt thereof according to any one of the preceding claims in the manufacture of a medicament for diagnosing and / or treating a disease or disorder characterized by overexpression or reduced expression of EphA2.

114. The peptide or a salt thereof according to any one of the preceding claims for use in diagnosing and / or treating a disease or disorder characterized by overexpression or reduced expression of EphA2.

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