EphA2-binding retention peptides and compositions containing same

Abstract

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

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 411,222, filed September 29, 2022. The entire contents of the above application, including any drawings and sequence listing, are expressly incorporated herein by reference.

[0002] joint research agreement The subject matter disclosed herein was developed and the claimed invention was made by 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 CFR § 1.9(e) in effect on or before the effective filing date of the claimed invention. One or more parties to the JRA consist of PeptiDream, Inc. (Kanagawa, Japan) and RayzeBio, Inc. (San Diego, CA, USA). The claimed invention was made as a result of activities conducted within the scope of the Joint Research Agreement.

[0003] The present technology relates to peptides that bind to Eph receptor tyrosine kinase A2 (EphA2) and compositions comprising such peptides. The invention also includes conjugates comprising the peptides conjugated to one or more effectors and / or functional groups, any substances, such as pharmaceutical compositions, comprising the peptide ligands and the substance conjugates, and the use of the peptide ligands and substance conjugates in the prevention, suppression, or treatment of diseases or disorders characterized by overexpression or underexpression of EphA2 in affected tissues, such as tumors, when EphA2 is overexpressed. [Background technology]

[0004] Eph receptor A2 (ephrin type A receptor 2; EphA2) is a member of the receptor tyrosine kinase family. Ephrin A, the ligand for EphA2, is a membrane protein known to be required for cell-cell interactions to transmit signals via EphA2. EphA2-associated signals are known to play an important role in cell proliferation or differentiation. Furthermore, EphA2 is known to be one of the important cancer-related proteins. EphA2 is overexpressed in some human tumor cells, and reduction of EphA2 expression levels using anti-EphA2 antibodies leads to cancer cell proliferation (Japanese Patent Publication No. 2010246546). Therefore, antibodies that bind to EphA2 are expected to be therapeutic agents for cancer. Furthermore, antibody-drug conjugates containing anti-EphA2 antibodies and anticancer drugs are expected to be therapeutic agents for cancer, such as those developed by Mediimmune (Medimmune LLC). However, such antibody-drug conjugates (ADCs) have not yet been released on the pharmaceutical market.

[0005] Recently, it has been known that drug-drug conjugate peptides (PDCs) are a solution. Due to the characteristics of peptides (insert scientific paper on PDs), peptides, especially cyclic peptides, can overcome the weaknesses of ADCs and become an alternative pharmaceutical component to ADCs.

[0006] Therefore, it can be a pharmaceutical ingredient for diseases associated with overexpression or underexpression of EphA2. Furthermore, peptides that bind to / have binding ability to EphA2 (EphA2-binding peptides) can be used to target and deliver low-molecular-weight compounds, medium-molecular-weight compounds, high-molecular-weight compounds, peptides, proteins, antibodies, nucleic acids, etc. to subjects with pharmacological effects on EphA2.

[0007] EphA2-binding peptides can be used to determine the distribution and quantity of EphA2 expression, for example, by measuring the binding of fluorescently labeled or tagged peptides to EphA2. Furthermore, the affinity of ligands for EphA2 or different species of EphA2 can be determined using EphA2-binding peptides.

[0008] Thus, novel EphA2-binding peptides and compositions comprising EphA2-binding peptides are both useful and desirable. Summary of the Invention [Means for solving the problem]

[0009] The invention described herein provides, inter alia, peptides (e.g., cyclic peptides) that bind to EphA2, particularly human EphA2, their linker-linked peptides, their conjugates, kits thereof (e.g., kits for use in methods for diagnosing diseases or disorders characterized by overexpression or underexpression of EphA2 by determining the expression level of EphA2); compositions (e.g., pharmaceutical compositions) comprising such EphA2-binding peptides or their conjugates, and methods of using them.

[0010] Particular, non-limiting, and exemplary aspects and embodiments of the invention described herein are provided below as numbered embodiments. As used herein, "(cyclic) peptide" means "a peptide, such as a cyclic peptide."

[0011] 1. A (cyclic) peptide having binding ability to ephrin type-A receptor 2 (EphA2), wherein the peptide comprises an amino acid sequence comprising one or several (e.g., 1 to 6) amino acid deletions, substitutions, and / or additions in the amino acid sequence of SEQ ID NO: 1: da-MeF-NL-Hgl-MeF-W1Me-V-W1Me-TEC (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof, wherein the (cyclic) peptide consists of 10 to 12 amino acid residues, or a pharmaceutically acceptable salt thereof.

[0012] 2. The (cyclic) peptide of embodiment 1, wherein 1 to 5 amino acids selected from the group consisting of the third N, the fourth L, the sixth MeF, the tenth T and the eleventh E of SEQ ID NO: 1 are deleted, optionally without further additions and / or substitutions.

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

[0014] 4. The (cyclic) peptide of any one of embodiments 1 to 3, wherein one or more amino acid residues selected from the second MeF, the sixth MeF, the eighth V and the eleventh E are substituted.

[0015] 5. The (cyclic) peptide of any one of embodiments 1 to 4, wherein the peptide comprises an amino acid sequence having a deletion of no more than 2 amino acids in amino acid sequence SEQ ID NO: 1, optionally without further additions and / or substitutions.

[0016] 6. The (cyclic) peptide of embodiment 5, wherein 1 to 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 further addition and / or substitution.

[0017] 7. A (cyclic) peptide having binding ability to ephrin type-A receptor 2 (EphA2), comprising 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) During the ceremony, X1 is an amino acid; X2 is an amino acid containing an aromatic ring, an N-methylated amino acid thereof, 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 an N-methylated amino acid thereof; 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 a hydrophilic amino acid (e.g., threonine (T) or a mutant thereof); X11 is absent or a hydrophilic amino acid; X12 is cysteine ​​(C) or a mutant thereof, a (cyclic) peptide, or a pharmaceutically acceptable salt thereof.

[0018] 8. The (cyclic) peptide of embodiment 7, wherein X3 is a hydrophilic amino acid.

[0019] 9. The (cyclic) peptide of embodiment 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.

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

[0021] 11. The (cyclic) peptide of embodiment 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).

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

[0023] 13. The (cyclic) peptide of embodiment 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).

[0024] 14. The (cyclic) peptide of any one of embodiments 7 to 13, wherein X6 is a hydrophilic amino acid.

[0025] 15. The (cyclic) peptide of embodiment 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).

[0026] 16. The (cyclic) peptide of any one of embodiments 7 to 15, wherein X11 is a hydrophilic amino acid.

[0027] 17. The (cyclic) peptide of embodiment 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. The (cyclic) peptide of any one of embodiments 1 to 17, wherein the peptide has an 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 represents F or an unsubstituted phenyl ring of F: (i) -OH, -CN, -C 1~3 a phenyl ring substituted with one or two substituents each independently selected from alkyl (e.g., —CH3), or (ii) -OH, -CN, -C 1~3 a 6-membered heteroaryl ring optionally substituted with one or two substituents each independently selected from alkyl (e.g., —CH3); and variants thereof in which F or a structural variant thereof 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 four or more carbon atoms in its side chain, including a straight, branched, or cyclic carbon chain), and 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 having a functional side chain (e.g., not glycine)); X6 is the N-methylated amino acid; X7 is W, Y, or a variant thereof (e.g., an amino acid having either a 6-membered aryl or heteroaryl, or a 9- or 10-membered bicyclic aryl or heteroaryl bonded to the alpha carbon through a carbon (e.g., a methylene group), where the 6-, 9-, and 10-membered heteroaryl have one heteroatom (e.g., N), and the 6-, 9-, and 10-membered aryl or heteroaryl are optionally substituted with one or two 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 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 having a functional side chain (e.g., not glycine)); 18. The (cyclic) peptide of any one of embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein X12 is C or a variant thereof.

[0029] 19. The (cyclic) peptide of any one of embodiments 1 to 18, wherein the peptide has an amino acid sequence salt of formula (Ia), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X12 Formula (Ia) During the ceremony, X1 is an amino acid (e.g., a D-amino acid); X2 is an amino acid containing an aromatic ring, an N-methylated amino acid thereof, 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 an N-methylated amino acid thereof; 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); 19. The (cyclic) peptide of any one of embodiments 1-18, or a pharmaceutically acceptable salt thereof, wherein X12 is C or a variant thereof.

[0030] 20. The (cyclic) peptide of any one of embodiments 1 to 18, wherein the peptide has an 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) During the ceremony, X1 is an amino acid (e.g., a D-amino acid); X2 is an amino acid containing an aromatic ring, an N-methylated amino acid thereof, 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 an N-methylated amino acid thereof; 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; 19. The (cyclic) peptide of any one of embodiments 1-18, or a pharmaceutically acceptable salt thereof, wherein X12 is C or a variant thereof.

[0031] twenty one. 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., linear or branched C 1~5 Alkyl-substituted G, C 3~7 G or C substituted with cycloalkyl 3~7 A) substituted with cycloalkyl; X5 is a hydrophilic L-amino acid, wherein the L-amino acid comprises 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, an N-methylated amino acid thereof, or a variant 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 one or two straight or branched chain C 1~5 Alkyl-substituted G, C 3~7 Cycloalkyl-substituted G, C3~7 A is cycloalkyl substituted, or a hydrophilic L-amino acid, where the hydrophilic L-amino acid comprises -NH, one or more -OH, -C(O)OH, -NHC(NH)NH, -NHC(O)NH, -C(O)NH, or -NHC(O)CH; 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 variants thereof (e.g., linear or branched C 1~5 L-amino acids containing -NHC(NH)NH, -NHC(O)NH, -C(O)NH, or -NHC(O)CH, optionally substituted with alkyl (Q, S, K, Cit, N, or T); X11 is absent, E, Q, R, Cit, K, D, or N, or a variant thereof; 21. The (cyclic) polypeptide of any one of embodiments 1 to 20, wherein X12 is C or a variant thereof.

[0032] 22. The (cyclic) peptide of any one of embodiments 1 to 21, wherein the peptide has an 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) During the ceremony, 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, Qglucamine, hCit, K, KAc, Aib, Alb, DapAc, OrnAc, A, T, aIT, 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 or E, Hgn, R, hArg, Cit, hCit, Hgl, Orn, D, N, Q, DapAc, OrnAc, DabAc, norCit; 22. The (cyclic) peptide of any one of embodiments 1-21, wherein X12 is C, hCys, CdMe, C3RMe, C3SMe, selenocysteine, dc, or penicillamine, or a pharmaceutically acceptable salt thereof.

[0033] twenty three. X7 is W1Me or a variant thereof, 23. The (cyclic) peptide of any one of embodiments 18 to 22, wherein X9 is W1Me or a variant thereof.

[0034] twenty four. X7 is W1Me, W1MeCl, W1MeBr, Na1, Na12, W1Et, 3Bzf, 3Bzt, F23dC, W1Me7N, or F23dMe; X8 is V, KCOpipzaa, N, Cit, hCit, KAc, DapAc, OrnAc, A, T, aIT, Aib, Alb, Qglucamine, Hgl, Q, E, Hgn, or K; 24. The (cyclic) peptide of any one of embodiments 18 to 23, wherein X9 is W1Me, Na11, W1Et, Na121N, 3Bzf, 3Bzt, Na118N, F23dMe, or F23dC.

[0035] 25. The (cyclic) peptide of any one of embodiments 1 to 17, wherein the peptide comprises an 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) During the ceremony, 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; 18. The (cyclic) peptide of any one of embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein X12 is C or a variant thereof (such as C).

[0036] 26. The (cyclic) peptide of any one of embodiments 1 to 17, 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) During the ceremony, 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; 18. The (cyclic) peptide of any one of embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein X12 is C or a variant thereof.

[0037] 27. A (cyclic) peptide having binding ability to ephrin type A receptor 2 (EphA2), wherein the peptide has 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, (In the formula, 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 an amino acid; X12 is cysteine ​​(C) or a variant thereof; and A (cyclic) peptide, optionally consisting of a linker connecting the peptide to a payload molecule.

[0038] 28. Amino acid variants are selected from amino acids having one, two, or three substituents based on the amino acid, the substituents being 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 The (cyclic) peptide of any one of embodiments 7 to 27, wherein the (cyclic) peptide is selected from aryl, C3-C6 cycloalkyl, 6-10 membered heterocycloalkyl, and 6-10 membered heteroaryl.

[0039] 29. The (cyclic) peptide of embodiment 28, wherein the variant is selected from amino acids having one or two substituents based on the amino acid, the substituents being 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 of any one of embodiments 7 to 29, wherein the variants are selected from amino acids that have similar hydrophilicity or hydrophobicity compared to the reference amino acid.

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

[0042] 32. The (cyclic) peptide of any one of embodiments 7 to 31, wherein the variant has a molecular weight that does not vary by more than 14, 28, 30, 45 or 60 g / mol compared to the reference amino acid.

[0043] 33. A (cyclic) peptide having binding ability to 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) During the ceremony, X1 is any D- or L-amino acid; X2 is [ka] wherein: Ring A2 is phenyl or a 6-membered heteroaryl (e.g., heteroaryl with 1 or 2 N); R X2 are each independently a halogen, -CN, -NO2, -OH, or -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 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally and independently selected from one or more R XA is replaced by; 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 indicates the point of attachment to X1; * X3 indicates the point of attachment to X3; X3 is [ka] 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 indicates the point of attachment to X2; * X4 indicates the point of attachment to X4; X4 is a hydrophobic amino acid (e.g., an amino acid having four or more carbon atoms in its side chain, including a straight, branched, or cyclic carbon chain), and X4 is C 1~3 optionally N-alkylated with an alkyl group; X5 is a hydrophilic L-amino acid, for example, an amino acid having the following structure: [ka] where: R NX5 is H, —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is optionally and independently selected from one or more R XA is replaced by; R X5 -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 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is optionally and independently selected from one or more R XA is replaced by; However, RN X5 and R X5At least one of the groups is -OH, -NH and -NH- (e.g., -NH-C(=NH)-NH, -CO-NH, -NH, -COOH, -C(OH)-C 0~6 Alkyl, -NH-CO-C 1~6 alkyl); * X4 indicates the point of attachment to X4; * X6 indicates the point of attachment to X6; The X6 is [ka] (e.g., N, F), where: R NX6 is H, C1-C6 alkyl or C1-C6 haloalkyl; R X6 -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; wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally and independently selected from the group consisting of one or more R XA is replaced by; * X5 indicates the point of attachment to X5; * X7 indicates the point of attachment to X7; The X7 is [ka] wherein: R NX7 is H, C1-C6 alkyl or C1-C6 haloalkyl; Ring A7 is aryl or heteroaryl; R X7 are each independently a halogen, -CN, -NO2, -OH, or -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)NRc 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 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally and independently selected from one or more R XA is replaced by; kx7 is 0, 1, 2 or 3; mx7 is 0, 1, 2, 3, 4 or 5; * X6 indicates the point of attachment to X6; * X8 indicates the point of attachment to X8; X8 is an L-amino acid having an -H on the α-amino group; X9 is [ka] wherein: R NX9 is H, C1-C6 alkyl or C1-C6 haloalkyl; Ring A9 is aryl or heteroaryl; R X9 are each independently a halogen, -CN, -NO2, -OH, or -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 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally and independently selected from one or more R XA is replaced by; kx9 is 0, 1, 2 or 3; mx9 is 0, 1, 2, 3, 4, or 5; * X8 indicates the point of attachment to X8; * XC represents (i) the point of attachment to X10 or (i) X12 if X10 and X11 are absent; X10 is absent or an L-amino acid; X11 is absent or is an L-amino acid; with the proviso that if X10 is absent, then X11 is also absent; X12 is an L-amino acid with 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, 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 b 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, 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 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; or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; 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; Optionally, the peptide is linked to the payload molecule via a linker, a (cyclic) peptide.

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

[0045] 35.R NX7 The (cyclic) peptide of embodiment 33 or 34, wherein

[0046] 36.Each R X7 The (cyclic) peptide of any one of embodiments 33 to 35, wherein mx7 is 0, 1, or 2; and mx8 is independently selected from -CH3, -ethyl, -Cl, and -F.

[0047] 37. The (cyclic) peptide of embodiment 33, wherein X7 is W1Me, Na11, Na12, W1Et, Na121N, 3Bzf, 3Bzt, Na115N, Na114N, Na124N, Na128N, F23dMe, F23dC, W1Me7N, or W1Me7Cl.

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

[0049] 39.X9 is [ka] and each R X9is independently selected from -OH, CN, NH2, C1-C3 alkyl, -Cl, -F, -Br, -CNH2, and -SO2F.

[0050] 40. [ka] but, [ka] 40. The (cyclic) polypeptide of any one of embodiments 33 to 39, wherein:

[0051] 41.R X9 are each independently a halogen, -CN, -NO2, -OH, or -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 of any one of embodiments 33-38, wherein X9 is W1Me, W, Na11, W1Et, Na121N, 3Bzf, 3Bzt, Na114N, Na118N, F23dMe, F23dC, or W1Et.

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

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

[0055] 45.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 The (cyclic) peptide of any one of embodiments 33 to 44, wherein said (cyclic) peptide is alkyl.

[0056] 46. X7 is W1Me, W1MeCl, W1MeBr, Na1, Na12, W1Et, 3Bzf, 3Bzt, F23dC, W1Me7N, or F23dMe; X8 is V, KCOpipzaa, Hse, N, Cit, hCit, KAc, DapAc, OrnAc, T, alT, Aib, Alb, Qglucamine, Hgl, E, Hgn, MeF, 3Py6NH2, W1Me, A, Q, or K; 34. The (cyclic) peptide of any one of embodiments 27 to 33, wherein X9 is W1Me, Na11, W1Et, Na121N, 3Bzf, 3Bzt, Na118N, F23dMe, or F23dC.

[0057] 47. X7 is W1Me; X8 is V; The (cyclic) peptide of any one of embodiments 24 to 46, wherein X9 is W1Me.

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

[0059] 49. The (cyclic) peptide of any one of embodiments 1 to 48, wherein the peptide or a pharmaceutically acceptable salt thereof has a cyclic structure with the amino acid and a cysteine ​​residue or variant thereof at the first residue X1, and the amino acid and the cysteine ​​residue or variant thereof in X1 form a covalent bond.

[0060] 50. The (cyclic) peptide of any one of embodiments 1-49, wherein the peptide is a monocyclic structure.

[0061] 51. The (cyclic) peptide of embodiment 50, wherein the amino acid X1 and cysteine ​​or a variant thereof form a covalent bond.

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

[0063] 53. The peptide of formula (I-1) has the structure of formula (I-2) [ka] 53. The (cyclic) peptide of embodiment 52, having the formula:

[0064] 54. The (cyclic) peptide of any one of embodiments 1 to 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 NOs: 1 to 171, or a sequence that has 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 to 171.

[0065] 55. The (cyclic) peptide of any one of embodiments 1 to 54, wherein the peptide or salt thereof (a) consists of an amino acid sequence selected from SEQ ID NOs: 1 to 171, or (b) is not SEQ ID NO: 1.

[0066] 56. The (cyclic) peptide of embodiment 55, wherein the peptide consists of an amino acid sequence selected from SEQ ID NOs: 1-122, 159-163 and 165-171, wherein the peptide has a cyclic structure with a cysteine ​​residue or a variant thereof at residue 12, and wherein the amino acid at X1 (e.g., a chloroacetylated amino acid) and the cysteine ​​residue or a variant thereof at residue 12 form a covalent bond (e.g., by reacting the chloroacetyl group in the amino acid at X1 with the cysteine ​​residue or a variant thereof).

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

[0068] 58. The peptide was analyzed by surface plasmon resonance (SPR) analysis. d 58. The (cyclic) peptide of any one of embodiments 1-57, having a binding affinity to human EphA2 of up to 100 nM as determined by

[0069] 59. The peptide was analyzed by surface plasmon resonance (SPR) analysis. d59. The (cyclic) peptide of embodiment 58, having a binding affinity for human EphA2 of at most 1 nM, as determined by

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

[0071] 61. The (cyclic) peptide of any one of embodiments 1 to 60, wherein the peptide interacts with 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.

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

[0073] 63. The peptide has a plasma half-life (T) 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. 1 / 2 63. The (cyclic) peptide of any one of embodiments 1 to 62, having the formula:

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

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

[0076] 66. The (cyclic) peptide of 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 of embodiment 66, wherein the linker is attached to the fifth amino acid residue, or X5.

[0078] 68. The (cyclic) peptide of embodiment 66, wherein the linker is attached to the eighth amino acid residue, or X8.

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

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

[0081] 71. The (cyclic) peptide of 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 of 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 of any one of embodiments 65-72, wherein the linker is a bond.

[0084] 74. The (cyclic) peptide of any one of embodiments 65-72, wherein the linker comprises 3 to 30 intervening atoms between the payload molecule and the peptide.

[0085] 75. The (cyclic) peptide of any one of embodiments 65-72, wherein the linker comprises 6 to 18 intervening atoms between the payload molecule and the peptide.

[0086] 76. The (cyclic) peptide of embodiment 74 or 75, wherein the intervening atoms comprise 1 to 6 nitrogens and 0 to 4 oxygens.

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

[0088] 78. The (cyclic) peptide according to embodiment 77, wherein the linker comprises one or more amino acids selected from lysine, alanine or phenylalanine residues.

[0089] 79. The (cyclic) peptide of any one of embodiments 65 to 72 and 74 to 78, wherein the linker comprises one or more structures selected from AEEA, AEEP, AEEEP, and AEEEEP.

[0090] 80. The linker has the structure of formula (II-1): [ka] 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 30Alkynylene, 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)-; Each R L are 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; The (cyclic) peptide of any one of embodiments 65 to 72, wherein n is 1 to 20.

[0091] 81. The linker comprises a structure of formula (II-1a): [ka] In the formula, L 1 and L 3 each independently represents -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 -, -NRL S(=O)2-, -S(=O)2NR L -, -C(=O)NR L S(=O)2- or -S(=O)2NR L C(=O)-; L 2 is absent or substituted or unsubstituted C1-C 30 Alkylene, or substituted or unsubstituted C1-C 30 The (cyclic)peptide according to embodiment 80, which is heteroalkylene.

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

[0093] 83.L 2 is a substituted or unsubstituted C1 to C 30 Alkylene, or substituted or unsubstituted C1-C 30 83. The (cyclic)peptide of embodiment 81 or 82, which is heteroalkylene.

[0094] 84.L 2 is a substituted or unsubstituted C1 to C 18 Alkylene, or substituted or unsubstituted C1-C 18 83. The (cyclic)peptide of embodiment 81 or 82, which is heteroalkylene.

[0095] 85.L 2 is -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 C1-C6 alkyl is optionally substituted with one or more substituents selected from -OH, -SH, oxo, amino, C6-C 10Aryl, 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 85. The (cyclic) peptide of any one of embodiments 81 to 84, optionally further substituted with one or more substituents selected from:

[0096] 86.L 3 The (cyclic) peptide of any one of embodiments 81 to 85, wherein is -NH-.

[0097] 87. The linker [ka] [ka] [ka] 82. The (cyclic) peptide according to embodiment 81, having the structure:

[0098] 88. The linker [ka] 82. The (cyclic) peptide according to embodiment 81, having the structure:

[0099] 89. The (cyclic) peptide of any one of embodiments 1-88, wherein the peptide is of formula (I) and wherein, when the peptide is bound to human EphA2, amino acid residue X7 is located less than 10 Å from Phe156 of human EphA2.

[0100] 90. The (cyclic) peptide of embodiment 89, wherein amino acid residue X7 is located less than 6 Å from Phe156.

[0101] 91. The (cyclic) peptide of embodiment 89, wherein amino acid residue X7 is located less than 4 Å from Phe156.

[0102] 92. The (cyclic) peptide of any one of embodiments 1 to 91, wherein the peptide is of formula (I) and wherein, when the peptide is bound to human EphA2, amino acid residue X9 is located less than 10 Å from Phe156 of human EphA2.

[0103] 93. The (cyclic) peptide of embodiment 92, wherein amino acid residue X9 is located less than 6 Å from Phe156.

[0104] 94. The (cyclic) peptide of embodiment 93, wherein the amino acid residue X9 is located less than 4 Å from Phe156.

[0105] 95. The (cyclic) peptide of any one of embodiments 1-94, wherein the peptide is of formula (I) and wherein, when the peptide is bound to human EphA2, amino acid residue X8 is located less than 10 Å from Phe156 of human EphA2.

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

[0107] 97. Having binding ability to ephrin type A receptor 2 (EphA2), SEQ ID NO: 1: da-MeF-NL-Hgl-MeF-W1Me-V-W1Me-TEC (SEQ ID NO: 1) A (cyclic) peptide that competes for binding to human EphA2 with a peptide having an amino acid sequence containing one or more amino acid deletions, substitutions or additions in the amino acid sequence of the above, or a pharmaceutically acceptable salt thereof.

[0108] 98. A (cyclic) peptide having binding ability to ephrin type-A receptor 2 (EphA2), which peptide competes for binding to human EphA2 with a peptide having the structure of formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) During the ceremony, X1 is an amino acid; X2 is an amino acid containing an aromatic ring, an N-methylated amino acid thereof, 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 an N-methylated amino acid thereof; 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 a hydrophilic amino acid (e.g., threonine (T) or a mutant thereof); X11 is absent or a hydrophilic amino acid; X12 is cysteine ​​(C) or a mutant thereof, a (cyclic) peptide, or a pharmaceutically acceptable salt thereof.

[0109] 99. A (cyclic) peptide having binding ability to 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, During the ceremony, 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 an amino acid; X12 is cysteine ​​(C) or a mutant thereof; The peptide is a (cyclic) peptide, or a pharmaceutically acceptable salt thereof, optionally linked to a payload molecule via a linker.

[0110] 100. The (cyclic) peptide of any one of embodiments 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 of embodiment 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 of any one of embodiments 97-101, wherein human EphA2 comprises the amino acid sequence of SEQ ID NO: 276 or SEQ ID NO: 277.

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

[0114] 104. A conjugate comprising the peptide or salt thereof according to any one of the preceding embodiments and a substance, wherein the substance is selected from the group consisting of a nucleotide, a small molecule, a medium-sized molecule (e.g., having a molecular weight of about 1,000 to 2,500 Da), a large molecule (e.g., having a molecular weight of more than 2,500 Da), a polymeric compound, a protein, a peptide, a tag, a biological fragment, a carrier comprising a pharmaceutical compound, or a combination thereof.

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

[0116] 106. The method of embodiment 105, wherein the disease or disorder is cancer.

[0117] 107. The method of embodiment 106, wherein the cancer is selected from glioblastoma, prostate cancer, lung cancer, breast cancer, gastric cancer, ovarian cancer, adenocarcinoma, colon cancer, esophageal cancer, multiple myeloma, and fibrosarcoma.

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

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

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

[0121] 111. The kit, tester or composition of embodiment 110 adapted for use in a method for diagnosing a disease or disorder characterized by overexpression or underexpression of EphA2.

[0122] 112. The kit, tester or composition of embodiment 110 or 111, wherein the sample is derived from a subject having a disease or disorder characterized by overexpression or underexpression of EphA2.

[0123] 113. Use of a peptide or 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 underexpression of EphA2.

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

[0125] In some embodiments, the peptides of the present technology are isolated peptides.

[0126] In some embodiments, the peptides of the present technology are purified peptides.

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

[0128] Because the peptides of the technology of the present invention have the binding ability to EphA2, the peptides can target and transport compounds that have pharmacological effects 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 skilled in the art upon review of the following description of specific embodiments in conjunction with the accompanying figures.

[0130] All features of the embodiments described in this disclosure are not mutually exclusive and can be combined with each other. For example, elements of one embodiment can be utilized in other embodiments without further recitation. Detailed descriptions of specific embodiments are provided below with reference to the accompanying drawings. [Brief explanation of the drawings]

[0131] [Figure 1] 1 illustrates an exemplary PDC of the present disclosure, wherein: [ka] represents the linker, and the peptide covalently attached to the payload, represented by the rounded rectangle, is shown inside the circle. [Figure 2] 1 shows a general synthesis scheme A of macrocyclic peptide I of the present invention. [Figure 3] 1 shows a general synthesis scheme B of the macrocyclic peptide II of the present invention. [Figure 4] 1 shows a general synthesis scheme C of the macrocyclic peptide II of the present invention. [Figure 5] 1 shows the synthesis scheme of PDC_EphA2-00007196-C004 (sequence number 224). [Figure 6] 6 shows the synthesis scheme of PDC_EphA2-00007196-C010 (SEQ ID NO: 231). Figure 6 discloses "bA-MeG-MeG-MeG-MeG-MeG-MeG-MeG-MeG-MeG" as SEQ ID NO: 279. DETAILED DESCRIPTION OF THE INVENTION

[0132] It should be understood that both the following general description and detailed description are exemplary and explanatory only and are not intended to limit the technology of the present application. As used herein, the use of the singular includes the plural unless otherwise stated. As used herein, the use of "or" means "and / or" unless otherwise stated. Furthermore, terms such as "element" or "component" encompass both elements and components comprising one unit and elements and components comprising two or more subunits, unless otherwise stated.

[0133] The headings used herein are for organizational purposes only and should not be construed in any way as limiting the subject matter described. All or any portion of the documents cited in this application, including but not limited to patents, patent applications, articles, books, and treatises, are expressly incorporated by reference, in whole or in part, from among the documents described herein.

[0134] The recitation herein of numerical ranges by endpoints is intended to include all numbers subsumed within that range (e.g., recitation of 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 4.32, and 5).

[0135] 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 "an agent" includes a plurality of such agents, reference to "the cell" includes reference to one or more cells (or cells) and equivalents thereof known to those of skill in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formula, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.

[0136] The terms "about" or "approximately" can mean within an acceptable error range of a particular value, as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 1 or 2 or more standard deviations, in accordance with practice in the art. Alternatively, "about" can mean within a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, within 5-fold, or within 2-fold of a value.

[0137] The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is to be interpreted in an open and inclusive sense, i.e., "including, but not limited to." The term "comprising" (and related terms such as "comprise," "comprises" or "having" or "including") is not intended to exclude that in other specific embodiments, embodiments, such as, for example, any composition of matter, composition, method, or process described herein, "consist of" or "consist essentially of" the described features.

[0138] "Amino" refers to the group -NH2.

[0139] "Cyano" refers to the radical -CN.

[0140] "Nitro" refers to the -NO2 group.

[0141] "Oxo" refers to the group =O.

[0142] "Imino" refers to the group =NH.

[0143] "Oximo" refers to the =N-OH group.

[0144] "Hydrazino" refers to the group =N-NH2.

[0145] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0146] "Hydroxyamino" refers to the group --NH--OH.

[0147] "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, where the carbonyl atom of the carbonyl group is the point of attachment. Unless stated otherwise in the specification, the alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, amide, or ester group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.

[0148] "Alkyl" refers to an optionally substituted straight-chain or optionally substituted branched-chain saturated hydrocarbon monoradical. An alkyl group can have 1 to about 20 carbon atoms, 1 to about 10 carbon atoms, or 1 to 6 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, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, and long chain alkyl groups such as heptyl, octyl, and the like. Wherever 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, however, this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is any of C1-C6 alkyls. 10 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 stated otherwise in the specification, alkyl groups are optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkyl is optionally substituted with oxo, halogen, —CN, —CF3, —OH, —OMe, —NH2, —NO2, or —C≡CH. In some embodiments, alkyl is optionally substituted with oxo, halogen, —CN, —CF3, —OH, or —OMe. In some embodiments, alkyl is optionally substituted with halogen.

[0149] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise in the specification, alkylene groups are optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylene is optionally substituted with oxo, halogen, -CN, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, alkylene is optionally substituted with oxo, halogen, -CN, -CF, -OH, or -OMe. In some embodiments, alkylene is optionally substituted with halogen. In some embodiments, alkylene is -CH-, -CHCH-, -CHCHCH-, or -CHCH(CH)CH-. In some embodiments, alkylene is -CH-. In some embodiments, alkylene is -CHCH-. In some embodiments, the alkylene is -CH2CH2CH2-.

[0150] "Alkenyl" refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double bonds. In some embodiments, an alkenyl group has 2 to about 10 carbon atoms, or 2 to about 6 carbon atoms. The group can be in either the cis or trans configuration about the double bond and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH), 1-propenyl (-CHCH=CH), isopropenyl [-C(CH)=CH], butenyl, 1,3-butadienyl, and the like. Whenever a numerical range such as "C2-C6 alkenyl" appears herein, it means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkenyl" where no numerical range is specified. In some embodiments, alkenyl refers to a C2-C6 alkenyl. 10Alkenyl is 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 stated otherwise in the specification, alkenyl groups are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkenyl is optionally substituted with oxo, halogen, —CN, —CF3, —OH, —OMe, —NH2, or —NO2. In some embodiments, alkenyl is optionally substituted with oxo, halogen, —CN, —CF3, —OH, or —OMe. In some embodiments, alkenyl is optionally substituted with halogen.

[0151] 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 connecting the remainder of the molecule to a radical group. In some embodiments, alkenylene is -CH=CH-, -CHCH=CH-, or -CH=CHCH-. In some embodiments, alkenylene is -CH=CH-. In some embodiments, alkenylene is -CHCH=CH-. In some embodiments, alkenylene is -CH=CHCH-.

[0152] "Alkynyl" refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple bonds. In some embodiments, an alkynyl group has from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadinyl, and the like. 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, although this definition also encompasses occurrences of the term "alkynyl" where no numerical range is specified. In some embodiments, alkynyl is a C2-C6 alkynyl group. 10 Alkynyl is 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 stated otherwise in the specification, alkynyl groups are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkynyl is optionally substituted with oxo, halogen, —CN, —CF3, —OH, —OMe, —NH2, or —NO2. In some embodiments, alkynyl is optionally substituted with oxo, halogen, —CN, —CF3, —OH, or —OMe. In some embodiments, alkynyl is optionally substituted with halogen. The term "alkynylene" refers to an optionally substituted straight-chain or optionally substituted branched-chain divalent hydrocarbon having one or more carbon-carbon triple bonds.

[0153] "Alkylamino" refers to a group of the formula -N(R a )2, where R a is an alkyl group as defined above, or two R acan be taken together with the nitrogen atom to form a substituted or unsubstituted C2-C7 heterosylalkyl ring. Unless stated otherwise in the specification, an alkylamino group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkylamino is optionally substituted with oxo, halogen, —CN, —CF3, —OH, —OMe, —NH2, or —NO2. In some embodiments, an alkylamino is optionally substituted with oxo, halogen, —CN, —CF3, —OH, or —OMe. In some embodiments, an alkylamino is optionally substituted with halogen.

[0154] "Alkoxy" is R a is an alkyl group defined as formula -OR a Unless stated otherwise in the specification, an alkoxy group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, —CN, —CF, —OH, —OMe, —NH, or —NO. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, —CN, —CF, —OH, or —OMe. In some embodiments, an alkoxy is optionally substituted with halogen.

[0155] "Aminoalkyl" refers to an alkyl group, 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.

[0156] The term "aryl" refers to a group containing at least one aromatic ring, where each of the atoms forming the ring is a carbon atom. An aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. In some embodiments, an aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Unless otherwise stated in the specification, the term "aryl" or the prefix "Ar-" (e.g., "aralkyl") is meant to include aryl groups that are optionally substituted. In some embodiments, an aryl group includes a partially reduced cycloalkyl group as defined herein (e.g., 1,2-dihydronaphthalene). In some embodiments, an aryl group includes a fully reduced cycloalkyl group as defined herein (e.g., 1,2,3,4-tetrahydronaphthalene). When an aryl includes a cycloalkyl group, the aryl is attached to the remainder of the molecule via an aromatic ring carbon atom. Aryl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring systems, which can include fused, spiro, or bridged ring systems. Unless stated otherwise in the specification, aryl can be optionally substituted with, for example, halogen, amino, alkylamino, aminoalkyl, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -S(O)NH-C1-C6 alkyl, etc. In some embodiments, aryl can be optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, -NO2, -S(O)2NH2, -S(O)2NHCH3, -S(O)2NHCH2CH3, -S(O)2NHCH(CH3), -S(O)2N(CH3), or -S(O)2NHC(CH3). In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.In some embodiments, the aryl is substituted with an alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl, and each alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl is independently unsubstituted or substituted with halogen, methyl, ethyl, —CN, —CF, —OH, —OMe, —NH, or —NO.

[0157] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic group, in which each of the atoms forming the ring (i.e., the skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl is saturated or partially unsaturated. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl is fused to an aromatic ring (in which case the cycloalkyl is attached via 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 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. Monocyclic cycloalkyl groups 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 cyclopentynyl. Polycyclic groups include, for example, adamantyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetranyl, decalinyl, 3,4-dihydronaphthalenyl-1(2H)-one, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl. Unless otherwise stated in the specification, cycloalkyl groups may be optionally substituted. Representative cycloalkyl groups include cycloalkyl groups containing 3 to 15 carbon atoms (C3-C6). 15 Cycloalkyl), 3 to 10 carbon atoms (C3 to C 10Examples of cycloalkyl include, but are not limited to, cycloalkyls having 3 to 8 carbon atoms (C-C cycloalkyl), 3 to 6 carbon atoms (C-C cycloalkyl), 3 to 5 carbon atoms (C-C cycloalkyl), or 3 to 4 carbon atoms (C-C cycloalkyl). In some embodiments, cycloalkyls are 3- to 6-membered cycloalkyls. In some embodiments, cycloalkyls are 5- to 6-membered cycloalkyls. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl or carbocycle include adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, 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]heptanyl. Examples of partially saturated cycloalkyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specified herein, cycloalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0158] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0159] "Haloalkyl" refers to an alkyl group, as defined above, substituted with one or more halogens. In some embodiments, the alkyl is substituted with one, two, or three halogens. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six halogens. Haloalkyl can include, for example, iodoalkyl, bromoalkyl, chloroalkyl, and fluoroalkyl. For example, "fluoroalkyl" refers to one or more fluoro groups, as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl portion of the fluoroalkyl group is optionally substituted as the alkyl group is defined above.

[0160] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or a combination thereof. The heteroalkyl is attached to the remainder of the molecule at 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 atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or a combination thereof, and the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CH2-O-CH2-, -CH2-N(alkyl)-CH2-, -CH2-N(aryl)-CH2-, -OCH2CHO-, -OCH2CHOCH2CHO-, or -OCH2CHOCH2CHOCH2CHO-. Unless stated otherwise in the specification, heteroalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, heteroalkyl is optionally substituted with halogen.

[0161] As used herein, "heteroalkylene" refers to a divalent heteroalkyl group. Examples of such heteroalkylene groups are, for example, -CH2-O-CH2-, -CH2-N(alkyl)-CH2-, -CH2-N(aryl)-CH2-, -OCH2CHO-, -OCH2CHOCH2CHO-, or -OCH2CHOCH2CHOCH2CHO-.

[0162] The term "heterocycloalkyl" refers to a cycloalkyl group containing at least one heteroatom, such as a heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified herein, a heterocycloalkyl group can be a monocyclic or bicyclic ring system, which can include fused (when fused with an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon, or sulfur atoms in a heterocyclyl group can be optionally oxidized. The nitrogen atom can be optionally quaternized. The heterocycloalkyl group can be partially or fully saturated. Examples of heterocycloalkyl groups include dioxolanyl, thienyl[1,3]dithianyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocycloalkyls have 2-12 carbons in the ring. In some embodiments, heterocycloalkyls have 2-10 carbons in the ring. In some embodiments, heterocycloalkyls have 2-10 carbons and 1 or 2 N atoms in the ring. In some embodiments, heterocycloalkyls have 2-10 carbons and 3 or 4 N atoms in the ring. In some embodiments, heterocycloalkyls have 2-12 carbons, 0-2 N atoms, 0-2 O atoms, 0-2 P atoms, and 0-1 S atoms in the ring.In some embodiments, a heterocycloalkyl has 2 to 12 carbons, 1 to 3 N atoms, 0 to 1 O atoms, and 0 to 1 S atoms in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) comprising the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise in the specification, a heterocycloalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0163] "Heteroaryl" refers to a ring system radical containing carbon atoms, 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 heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Illustrative examples of bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl, or furyl. In some embodiments, heteroaryl contains 0 to 6 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 4-6 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, 0-1 P atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring.In some embodiments, heteroaryl is a C1-C9 heteroaryl. In some embodiments, heteroaryl is a C1-C5 heteroaryl. In some embodiments, monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl groups are C6-C9 heteroaryl. In some embodiments, heteroaryl groups include a partially reduced cycloalkyl or heterocycloalkyl group as defined herein (e.g., 7,8-dihydroquinoline). In some embodiments, heteroaryl groups include a fully reduced cycloalkyl or heterocycloalkyl group as defined herein (e.g., 5,6,7,8-tetrahydroquinoline). When heteroaryl includes a cycloalkyl or heterocycloalkyl group, the heteroaryl is bonded to the remainder of the molecule via a heteroaromatic ring carbon or heteroatom. Heteroaryl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring systems, which can include fused, spiro, or bridged ring systems. Unless stated otherwise in the specification, heteroaryl is optionally substituted with, for example, halogen, amino, nitrile, optionally substituted with nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, heteroaryl is optionally substituted with halogen.

[0164] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical entity that is embedded in or appended to a molecule.

[0165] As used herein, the terms "treat," "prevent," "ameliorate," and "inhibit," as well as terms derived therefrom, do not necessarily imply 100% or complete treatment, prevention, amelioration, or inhibition. Rather, the degree of treatment, prevention, amelioration, and inhibition may vary, and these will be recognized by those of skill in the art as having potential benefit or therapeutic effect. In this regard, the disclosed methods can provide any level of treatment, prevention, amelioration, or inhibition of a disorder in a mammal. For example, a disorder, including its symptoms or condition, may be alleviated by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. Furthermore, the treatment, prevention, amelioration, or inhibition provided by the methods disclosed herein can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of a disorder, e.g., cancer or inflammatory disease.

[0166] In certain embodiments, "treating" includes the concept of "alleviating," 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 associated side effects. In certain embodiments, the term "treating" also encompasses the concept of "managing," which refers to reducing the severity or delaying the recurrence of a particular disease or disorder in a patient, e.g., extending the period of remission in a patient afflicted with a disease.

[0167] In certain embodiments, the terms "prevent" or "preventing" in relation to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in a treated sample compared to an untreated control sample, or delays the onset of or reduces the severity of one or more symptoms of the disorder or condition compared to an untreated control sample.

[0168] The term "therapeutically effective amount" as used herein refers to an amount effective at the dosage and duration necessary to achieve the desired therapeutic result. The therapeutically effective amount of a composition may vary depending on factors such as the condition, age, sex, and weight of the individual, and the ability of the protein to induce a desired response in the individual. A therapeutically effective amount may also be an amount that exceeds any toxic or harmful effects of the composition that would have a beneficial effect on treatment.

[0169] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl" as defined above. Furthermore, optionally substituted groups can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.).

[0170] As used herein, the term "substituent" refers to a positional variable on an atom of a core molecule that is substituted 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 that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. Those of skill in the art should note that any carbon and heteroatom having an apparently unsatisfied valence as described or shown herein is assumed to have a sufficient number of hydrogen atoms to satisfy the valences described or shown. In certain cases, one or more substituents having a double bond (e.g., "oxo" or "=O") as a point of attachment may be described, shown, or listed herein within a substituent, and the structure may show only a single bond as the point of attachment to the core structure. Those of skill in the art will understand that although only single bonds are shown, double bonds are intended for those substituents.

[0171] For the purposes of this disclosure, one event of "substitution" of an amino acid or amino acid sequence is not considered to be two separate events of one deletion and one addition. Thus, for the avoidance of doubt, by way of example, a sequence change of "up to two deletions, substitutions and / or additions" includes one deletion and one substitution, one deletion and one addition (at different positions), one substitution and one addition, one deletion only, one substitution only, one addition only, two deletions, two substitutions, two additions, etc. The deletion, addition, or substitution positions may be at either or both ends of the peptide, or in the middle of the peptide.

[0172] The terms "optionally substituted" or "substituted" mean that the referenced group is optionally substituted with one or more further groups individually and independently selected from D, halogen, -CN, -NH, -NH(alkyl), -N(alkyl), -OH, -COH, -COalkyl, -C(=O)NH, -C(=O)NH(alkyl), -C(=O)N(alkyl), -S(=O)NH, -S(=O)NH(alkyl), -S(=O)N(alkyl), alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, the optional substituents are independently selected from D, halogen, —CN, —NH, —NH(CH), —N(CH), —OH, —COH, —CO(C-C alkyl), —C(═O)NH, —C(═O)NH(C-C alkyl), —C(═O)N(C-C alkyl), —S(═O)NH, —S(═O)NH(C-C alkyl), —S(═O)N(C-C alkyl), C-C alkyl, C-C cycloalkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C alkoxy, C-C fluoroalkoxy, —SC-C alkyl, —S(═O)C-C alkyl, and —S(═O)C-C alkyl. In some embodiments, optional substituents are independently selected from D, halogen, -CN, -NH, -OH, -NH(CH), -N(CH), -NH(cyclopropyl), -CH, -CHCH, -CF, -OCH, and -OCF. In some embodiments, substituents are substituted with one or two of the foregoing groups. In some embodiments, optional substituents on an (acyclic or cyclic) aliphatic carbon atom include oxo (=O). When referring to the number of substituents, the term "one or more" means from one substituent to the highest possible number of substitutions, i.e., from replacing one hydrogen to replacing all hydrogens with substituents.

[0173] The term "unsubstituted" means that the specified group bears no substituents.

[0174] Certain compounds described herein may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the present disclosure.

[0175] Unless otherwise stated, structures depicted herein are also intended to include all stereochemical forms of the structure, i.e., the R and S configurations of each asymmetric center. Accordingly, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0176] As used herein, the term "peptide" refers to a compound containing two or more amino acids. The peptides described herein may contain one or more unnatural amino acids. The term "peptide" also encompasses peptidomimetics. In this disclosure, the term "amino acid" is used in its broadest sense and encompasses not only natural amino acids, but also their derivatives and artificial amino acids. For example, the term "amino acid" encompasses unnatural amino acids.

[0177] As used herein, the term "unnatural amino acid" refers to an amino acid other than the 20 standard amino acids, including 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).

[0178] As used herein, the term "protein" refers to a polypeptide (i.e., a chain of at least three amino acids linked together by peptide bonds). A protein may include moieties other than amino acids (e.g., may be a glycoprotein, proteoglycan, etc.) and / or may be processed or modified in other ways. A protein may be an entire polypeptide (with or without a signal sequence) that is produced by and / or active in a cell. In some embodiments, a protein is or includes a characteristic portion, such as a polypeptide, that is produced by and / or active in a cell. A protein may include two or more polypeptide chains. For example, the polypeptide chains may be linked by one or more disulfide bonds or may be linked by other means.

[0179] The term "peptidomimetic" or "mimetics" refers to biologically active compounds that mimic the biological activity of peptides or proteins but are not completely peptidic in 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 completely peptidic, such as pseudopeptides, semi-peptides, and peptoids. Whether completely or partially non-peptidic, the peptidomimetics described herein can provide a spatial arrangement of reactive chemical moieties that closely resembles the three-dimensional arrangement of active groups in the target amino acid sequence or target molecule on which the peptidomimetic is based. As a result of this similar active site geometry, peptidomimetics can affect biological systems similar to the biological activity of the target entity.

[0180] In some embodiments, peptidomimetics are highly similar in both three-dimensional shape and biological activity to the target amino acid sequence or target molecule on which they are based. One example is described in the paper "Tritiated D-ala-Peptide T Binding," Smith C.S. et al., Drug Development Res., 15, pp. 371-379 (1988). A second approach is to alter the cyclic structure for stability, such as N-C interchain imides and lactams (Ede et al., in Smith and Rivier (Eds.), "Peptides: Chemistry and Biology," Escom, Leiden (1991), pp. 268-270). An example of this is provided in conformationally restricted thymopentin-like compounds, such as those disclosed in U.S. Pat. No. 4,457,489. A third approach is to replace peptide bonds in the target entity with pseudopeptide bonds that confer resistance to proteolysis.

[0181] 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 subrange 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, as well as all intermediate decimal values ​​between the foregoing integers, e.g., 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to subranges, "nested subranges" extending from either endpoint of the range are specifically contemplated. For example, nested subranges of the exemplary range of 1 to 50 could 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.

[0182] As used herein, C1-C x(or C 1~x ) is C1~C2, C1~C3...C1~C x By way of example only, a group designated as "C1-C4" indicates that the moiety contains 1 to 4 carbon atoms, i.e., 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. 1~4 "Alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl group, i.e., the alkyl group is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl. Also, by way of example, C0-C2 alkylene includes a direct bond, -CH2-, and -CH2CH2- linkages.

[0183] As used herein, the term "cyclized" or "cyclization" means that two amino acids separated from each other by at least one amino acid are joined to each other directly or indirectly in a peptide to form a ring structure in the molecule. In some cases, the two amino acids are joined via a linker or the like.

[0184] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees, and other ape and monkey species; livestock animals such as cows, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals including rodents such as rats, mice, and guinea pigs. In one aspect, the mammal is a companion animal such as a dog or cat. In one aspect, the mammal is a human.

[0185] The term "therapeutically effective amount" as used herein refers to an amount effective at an administration dose to achieve a desired therapeutic result. The therapeutically effective amount of a composition may vary depending on the individual's condition (e.g., age, sex, and weight), the conjugate, and the method of administration (e.g., oral or parenteral).

[0186] Percent sequence identity can be calculated using computer programs 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, for example, DW Mount, 2001, Bioinformatics: Sequence and Genome Analysis, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY). BLASTP and TBLASTN programs are publicly available from NCBI and other sources. The Smith Waterman algorithm can also be used to determine percent identity. Exemplary parameters for amino acid sequence comparison include: 1) the algorithm from Needleman and Wunsch (J. Mol. Biol., 48:443-453 (1970)); 2) the BLOSSUM62 comparison matrix from Hentikoff and Hentikoff (Proc. Nat. Acad. Sci. USA., 89:10915-10919 (1992)); 3) gap penalty = 12; and 4) gap length penalty = 4. A useful program using these parameters is published as the "gap" program (Genetics Computer Group, Madison, Wis.). The aforementioned parameters are the default parameters for polypeptide comparisons (no penalty for end gaps). Alternatively, polypeptide sequence identity can be calculated using the following formula: % identity - (number of identical residues) / (length of alignment in amino acid residues). * 100. In this calculation, the alignment length includes internal gaps but does not include terminal gaps.

[0187] It is understood that certain features of the present disclosure that are described for clarity in the context of separate embodiments can also be provided in combination in a single embodiment. Conversely, various features of the present disclosure that are described for brevity in the context of a single embodiment can also be provided separately or in any suitable subcombination. For example, a conjugate of the present disclosure can include any peptide ligand described herein (e.g., a peptide ligand of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), or (Ic), or Table 1), any payload molecule described herein, optionally a linker described herein (e.g., a linker of formula (II-1), (II-1a), (II-1b), or (II-2)), and optionally a payload molecule described herein. In another example, a peptide of formula (I) (or any other formula, such as (III-1) and (III-2)) can include the X1-X12 amino acids described herein, with any combination of amino acid embodiments being encompassed by the present disclosure (in some cases, they are described in connection with separate embodiments).

[0188] Unless otherwise defined, the terms used in connection with analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein, as well as the procedures and techniques therefor, are well known and commonly used in the art. Standard techniques may be used for chemical synthesis and chemical analysis. Definitions of such techniques and procedures can be found, for example, in K. J. Jensen, P. T. Shelton, S. L. Pedersen, Peptide Synthesis and Applications, 2nd Edition, Springer, 2013, which are incorporated herein by reference for all purposes. All patents, applications, published applications, and other publications, as well as other data, mentioned throughout this disclosure are incorporated herein by reference where permitted.

[0189] Abbreviation: Unless otherwise specified herein, the following abbreviations are used in accordance with the following meanings: Alloc allyloxycarbonyl aq. aqueous solution Biotin-OSu Biotin N-hydroxysuccinimide ester (CAS 35013-72-0) Boc tert-butyloxycarbonyl ClAcOH chloroacetic acid ClAcOSu N-Succinimidyl 2-chloroacetate (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 (CAS 14970-87-7) EDCI-HCl N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (CAS 25952-53-8) eq equivalent Et Ethyl Et3N, TEA Triethylamine (CAS 121-44-8) Fmoc 9-Fluorenylmethoxycarbonyl hr time HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (CAS 148893-10-1) HOSu N-hydroxysuccinimide (CAS 6066-82-6) iPrOH / IPA isopropanol M molar concentration min 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 succinimidyl SulfoCy5 Sulfocyanine 5 tert third grade TFA Trifluoroacetic acid (CAS 76-05-1) TIS Triisopropylsilane (CAS 6485-79-6) TR retention time Trt trityl.

[0190] peptide: In one aspect, the present disclosure relates to peptides (e.g., binding peptides) that have binding ability to Ephrin type-A receptor 2 (EphA2). The EphA2 can be mammalian EphA2. The EphA2 can be human EphA2. The EphA2 can be wild-type or mutant EphA2. In some embodiments, the conjugates of the present disclosure comprise two or more peptides, which can be the same or different. The peptides can be linear or cyclic. In some embodiments, the peptides are monocyclic. The peptides can comprise any suitable number of amino acid residues. In some embodiments, the peptides comprise 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 peptides comprise 5 to 14 amino acid residues. In some embodiments, the peptides comprise 7 to 12 amino acid residues. In some embodiments, the peptides comprise 8 to 12 amino acid residues. In some embodiments, the peptides comprise 8 to 10 amino acid residues. In some embodiments, the peptide comprises 7-13 amino acid residues. In some embodiments, the peptide comprises 12-15 amino acid residues. In some embodiments, the peptide comprises 13-14 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 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 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 of 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. The peptides described herein can be binding peptides that bind to EphA2. In some embodiments, the binding peptide consists of 6-20 amino acid residues. In some embodiments, the binding peptide consists of 7-12 amino acid residues. In some embodiments, the binding peptide consists of 10-12 amino acid residues. In some embodiments, the binding peptide consists of 8-12 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.

[0191] In one aspect, described herein is a peptide (e.g., a cyclic peptide) having binding ability to Ephrin type-A receptor 2 (EphA2), wherein the peptide is selected from the group consisting of SEQ ID NO:1: A peptide (e.g., a cyclic peptide) comprising an amino acid sequence containing one or several (e.g., 1 to 6) amino acid deletions, substitutions, and / or additions in the amino acid sequence of da-MeF-NL-Hgl-MeF-W1Me-V-W1Me-TEC (SEQ ID NO: 1); or a pharmaceutically acceptable salt thereof. Optionally, the (cyclic) peptide consists of 10 to 12 amino acid residues.

[0192] In some embodiments, the (cyclic) peptide consists of 10 to 12 amino acid residues.

[0193] In some embodiments, the peptide comprises an amino acid sequence containing a total of six or fewer deletions, substitutions, and / or additions of one or several amino acids among the amino acid sequence of SEQ ID NO: 1. In some embodiments, the peptide comprises an amino acid sequence containing five or fewer deletions, substitutions, and / or additions of one or several amino acids among the amino acid sequence of SEQ ID NO: 1. In some embodiments, the peptide comprises an amino acid sequence containing four or fewer deletions, substitutions, and / or additions of one or several amino acids among the amino acid sequence of SEQ ID NO: 1. In some embodiments, the peptide comprises an amino acid sequence containing three or fewer deletions, substitutions, and / or additions of one or several amino acids among the amino acid sequence of SEQ ID NO: 1. In some embodiments, the peptide comprises an amino acid sequence containing two or fewer deletions, substitutions, and / or additions of one or several amino acids among the amino acid sequence of SEQ ID NO: 1. In some embodiments, the peptide comprises an amino acid sequence containing one or fewer deletions, substitutions, and / or additions of one or several amino acids among the amino acid sequence of SEQ ID NO: 1. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. The deletions, additions, or substitutions can be at one or both ends of the peptide, or in the middle of the peptide.

[0194] In some embodiments, the peptide comprises an amino acid sequence in which 1 to 5 amino acids selected from the group consisting of the third N, the fourth L, the fifth Hgl, the sixth MeF, the tenth T, and the eleventh E of 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 the third N, the fourth L, the fifth Hgl, the sixth MeF, the tenth T, and the eleventh E of SEQ ID NO: 1 are deleted in the peptide. In some embodiments, the third N is deleted. In some embodiments, the fourth L is deleted. In some embodiments, the fifth Hgl is deleted. In some embodiments, the sixth MeF is deleted. In some embodiments, the eleventh E is deleted. In some embodiments, the peptide comprises an amino acid sequence in which 1 to 5 amino acids selected from the group consisting of the third, fourth, fifth, sixth, tenth, and eleventh amino acids of 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 the amino acids at positions 3, 4, 5, 6, 10, and 11 of SEQ ID NO:1 have been deleted in the peptide. In some embodiments, the 3rd amino acid has been deleted. In some embodiments, the 4th amino acid has been deleted. In some embodiments, the 5th amino acid has been deleted. In some embodiments, the 6th amino acid has been deleted. In some embodiments, the 10th amino acid has been deleted. In some embodiments, the 11th amino acid has been deleted. In certain embodiments, the peptide has a deletion of 1 to 5 amino acids of SEQ ID NO:1 and no additional residue additions. In certain embodiments, the peptide has a deletion of 1 to 5 amino acids of SEQ ID NO:1 and no additional residue substitutions. In certain embodiments, the peptide has a deletion of 1 to 5 amino acids of SEQ ID NO:1 and no additional residue additions or substitutions. In certain embodiments, the peptide has a deletion of 1 to 5 amino acid residues of SEQ ID NO:1 and no additional residue additions. In certain embodiments, the peptide has a deletion of 1 to 5 amino acid residues of SEQ ID NO:1 and no residue substitutions.In certain embodiments, the peptide has a deletion of 1 to 5 amino acid residues of SEQ ID NO:1, and no residue additions or substitutions.

[0195] In one aspect, described herein is a peptide (e.g., a cyclic peptide) having binding ability to Ephrin type-A receptor 2 (EphA2), wherein the peptide has an amino acid sequence represented by 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, an N-methylated amino acid thereof, 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 an N-methylated amino acid thereof; 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 a hydrophilic amino acid (e.g., threonine (T) or a mutant thereof); X11 is absent or a hydrophilic amino acid; X12 is a (cyclic) peptide which is cysteine ​​(C) or a mutant thereof, or a pharmaceutically acceptable salt thereof.

[0196] In certain embodiments, X3 is a hydrophilic amino acid. In certain embodiments, X3 is a charged side chain (e.g., K or a variant thereof), a polar, uncharged side chain (e.g., Q, Cit, N, or a variant thereof), or G, A, or a variant thereof. In certain embodiments, X4 is a hydrophobic amino acid. In certain embodiments, X4 is an amino acid comprising a hydrophobic side chain (e.g., L) or an amino acid comprising a polar, uncharged side chain (e.g., Cit or a variant thereof). In certain embodiments, X5 is a hydrophilic amino acid. In certain embodiments, 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). In certain embodiments, X6 is a hydrophilic amino acid. In certain embodiments, 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). In certain embodiments, X11 is a hydrophilic amino acid. In certain embodiments, 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).

[0197] In one aspect, described herein is a peptide having binding ability to Ephrin type-A receptor 2 (EphA2), wherein the peptide has an amino acid sequence represented by formula (I), or a pharmaceutically acceptable salt thereof: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) During the ceremony, X1 is an amino acid; X2 represents F or an unsubstituted phenyl ring of F: (i) -OH, -CN, -C 1~3 a phenyl ring substituted with one or two substituents each independently selected from alkyl (e.g., —CH3), or (ii) -OH, -CN, -C 1~3a 6-membered heteroaryl ring optionally substituted with one or two substituents each independently selected from alkyl (e.g., —CH3); and variants thereof in which F or a structural variant thereof 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 four or more carbon atoms in its side chain, including a straight, branched, or cyclic carbon chain), and 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 with a functional side chain, e.g., not glycine); X6 is the N-methylated amino acid; X7 is W, Y, or a variant thereof (e.g., an amino acid having either a 6-membered aryl or heteroaryl, or a 9- or 10-membered bicyclic aryl or heteroaryl bonded to the alpha carbon through a carbon (e.g., a methylene group), the 6-, 9-, and 10-membered heteroaryl having one heteroatom (e.g., N), wherein the 6-, 9-, and 10-membered aryl or heteroaryl is optionally substituted with one or two 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 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 having a functional side chain (e.g., not glycine)); X12 is a (cyclic) peptide which is C or a variant thereof, or a pharmaceutically acceptable salt thereof.

[0198] In some embodiments of Formula (I), both X10 and X11 are present. In some embodiments of Formula (I), both X10 and X11 are absent.

[0199] In some embodiments, described herein are peptides (e.g., cyclic peptides) 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, W or a variant thereof, or an N-methylated amino acid; X3 is absent, N, Q, Cit or a mutant thereof, G, Aib, Hgn, K or a mutant thereof, Ala, or da; X4 is absent or is a straight or branched chain C 1~5 Alkyl-substituted G and C 3~7 A substituted with cycloalkyl, or Cit or variants thereof; X5 is absent, a hydrophilic amino acid, or an amino acid having a functional side chain (e.g., Dab, Dap, R, E), where hydrophilic amino acids include L-amino acids including -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, 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 one or two straight or branched chain C 1~5 Alkyl-substituted G and C 3~7 G, C substituted with cycloalkyl 3~7A is a cycloalkyl-substituted or hydrophilic amino acid, where the hydrophilic amino acid includes an L-amino acid containing -NH, one or more -OH, -C(O)OH, -NHC(NH)NH, -NHC(O)NH, -C(O)NH, -NHC(O)CH; or the hydrophilic amino acid includes 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., linear or branched C 1~5 T optionally substituted with alkyl), 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 mutant thereof, Cit or a mutant thereof, Hgl, K or a mutant thereof, D, N, or Q; X12 is a peptide of Formula (I) (eg, a cyclic peptide) that is C or a variant thereof, or a pharmaceutically acceptable salt thereof.

[0200] In some embodiments of the peptide of formula (I), or a pharmaceutically acceptable salt thereof, 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, Qglucamine, 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 or E, Hgn, R, hArg, Cit, hCit, Hgl, Orn, D, N, Q, DapAc, OrnAc, DabAc, norCit; X12 is C, hCys, CdMe, C3RMe, C3SMe, selenocysteine, dc, or penicillamine.

[0201] In some embodiments of the peptide of formula (I), or a pharmaceutically acceptable salt thereof, X7 is W1Me or a variant thereof; X9 is W1Me or a mutant thereof.

[0202] In some embodiments of the peptide of formula (I), or a pharmaceutically acceptable salt thereof, X7 is W1Me, W1MeCl, W1MeBr, Na1, Na12, W1Et, 3Bzf, 3Bzt, F23dC, W1Me7N, or F23dMe; X8 is V, KCOpipzaa, N, Cit, hCit, KAc, DapAc, OrnAc, A, T, aIT, Aib, Alb, Qglucamine, Hgl, Q, E, Hgn, or K; X9 is W1Me, Na11, W1Et, Na121N, 3Bzf, 3Bzt, Na118N, F23dMe, or F23dC.

[0203] In some embodiments of the peptide of formula (I), or a pharmaceutically acceptable salt thereof, X7 is W1Me; X8 is V; X9 is W1Me.

[0204] In one aspect, described herein is a peptide (e.g., a cyclic peptide) having binding ability to Ephrin type-A receptor 2 (EphA2), wherein the peptide has an amino acid sequence represented by Formula (I), or a pharmaceutically acceptable salt thereof: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) During the ceremony, X1 is any amino acid (e.g., a D-amino acid); X2 is an amino acid containing an aromatic ring or a substitution thereof, an N-methylated amino acid, or a substitution thereof; X3 is absent, N or a substitution thereof; X4 is absent or any hydrophobic amino acid or 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, an N-methylated amino acid thereof, or a substitution thereof; X7 is W or a substitution thereof; X8 is V, a hydrophilic amino acid or a substitution thereof, an N-methylated amino acid, or an amino acid having a functional side chain; X9 is W or a substitution thereof; X10 is absent, T or a substitution thereof; X11 is absent or any hydrophilic amino acid or an amino acid having a functional side chain; X12 is a peptide (eg, a cyclic peptide) that is C or a substitution thereof, or a pharmaceutically acceptable salt thereof.

[0205] In some embodiments, described herein is a peptide (e.g., a cyclic peptide) having an amino acid sequence represented by Formula (I), or a pharmaceutically acceptable salt thereof: 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; X3 is absent, N, or a mutant thereof; X4 is absent or any hydrophobic amino acid or variant thereof; X5 is absent, a hydrophilic amino acid or variant 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, or an N-methylated amino acid thereof; X7 is W or a variant thereof; X8 is V, a hydrophilic amino acid or variant thereof, an N-methylated amino acid, or an amino acid having a functional side chain; X9 is W or a variant thereof; X10 is absent, T, or a mutant thereof; X11 is absent or any hydrophilic amino acid or an amino acid having a functional side chain; X12 is a peptide (eg, a cyclic peptide) that is C or a variant thereof, or a pharmaceutically acceptable salt thereof.

[0206] In some embodiments, described herein is a peptide of formula (I), or a pharmaceutically acceptable salt thereof, wherein: X1 is any 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 mutant thereof), G, Aib, Hgn, or Ala, or a mutant thereof (e.g., da); X4 is absent, a hydrophobic amino acid, or a hydrophilic amino acid (e.g., Cit or a mutant thereof); X5 is absent, a hydrophilic amino acid, or an amino acid having a functional side chain; X6 is absent, a hydrophilic amino acid, 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 variant thereof); X11 is absent, a hydrophilic amino acid, or an amino acid having a functional side chain; X12 is a peptide of formula (I), which is C or a variant thereof, or a pharmaceutically acceptable salt thereof.

[0207] In some embodiments, described herein are peptides (e.g., cyclic peptides) of Formula (I), or pharmaceutically acceptable salts thereof: 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 mutant thereof), G, Aib, Hgn, or Ala, or a mutant 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 variants 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; X12 is a peptide of Formula (I) (eg, a cyclic peptide) that is C or a variant thereof, or a pharmaceutically acceptable salt thereof.

[0208] In some embodiments, described herein are peptides (e.g., cyclic peptides) of Formula (I), or pharmaceutically acceptable salts thereof: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) During the ceremony, 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 a peptide of formula (I) (e.g., a cyclic peptide) that is C or a variant thereof (e.g., C), or a pharmaceutically acceptable salt thereof.

[0209] In some embodiments, described herein is a peptide (e.g., a cyclic peptide) of Formula (Ia), or a pharmaceutically acceptable salt thereof: X1-X2-X3-X4-X5-X6-X7-X8-X9-X12 Formula (Ia) During the ceremony, 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; X12 is a peptide of Formula (I) (eg, a cyclic peptide) that is C or a variant thereof, or a pharmaceutically acceptable salt thereof.

[0210] In some embodiments, described herein is a (cyclic) peptide having binding ability to ephrin type-A receptor 2 (EphA2), consisting 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, During the ceremony, 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 an amino acid; X12 is a (cyclic) peptide which is cysteine ​​(C) or a mutant thereof, or a pharmaceutically acceptable salt thereof.

[0211] 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) (In the formula, 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 mutant thereof; X4 is any hydrophobic amino acid or variant thereof; X5 is a hydrophilic amino acid or a variant thereof; X6 is absent, a hydrophilic amino acid, 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 variant thereof, or an N-methylated amino acid; X9 is W or a variant thereof; X10 is absent, T, or a mutant thereof; X11 is absent or any hydrophilic amino acid; X12 is a peptide of formula (I), which is C or a variant thereof, or a pharmaceutically acceptable salt thereof.

[0212] In one aspect, described herein is a linkered peptide or conjugate comprising: (a) a (cyclic) peptide having a binding ability to ephrin type-A receptor 2 (EphA2), wherein the peptide has an amino acid sequence of formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) (In the formula, X1 is any D- or L-amino acid; X2 is [ka] wherein: Ring A2 is phenyl or a 6-membered heteroaryl (e.g., heteroaryl with 1 or 2 N); R X2 are each independently a halogen, -CN, -NO2, -OH, or -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 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally and independently selected from one or more R XA is replaced by; 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 indicates the point of attachment to X1; * X3 indicates the point of attachment to X3; X3 is [ka] 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 indicates the point of attachment to X2; * X4 indicates the point of attachment to X4; X4 is a hydrophobic amino acid (e.g., an amino acid having four or more carbon atoms in its side chain, including a straight, branched, or cyclic carbon chain), and X4 is C 1~3 optionally N-alkylated with an alkyl group; X5 is a hydrophilic L-amino acid, for example, an amino acid having the following structure: [ka] where: R NX5 is H, —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is optionally and independently selected from one or more R XA is replaced by; R X5 -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)Ra , -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 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is optionally and independently selected from one or more R XA is replaced by; However, RN X5 and R X5 At least one of the groups is -OH, -NH and -NH- (e.g., -NH-C(=NH)-NH, -CO-NH, -NH, -COOH, -C(OH)-C 0~6 Alkyl, -NH-CO-C 1~6 alkyl); * X4 indicates the point of attachment to X4; * X6 indicates the point of attachment to X6; The X6 is [ka] (e.g., N, F), where: R NX6 is H, C1-C6 alkyl or C1-C6 haloalkyl; R X6-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; wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally and independently selected from the group consisting of one or more R XA is replaced by; * X5 indicates the point of attachment to X5; * X7 indicates the point of attachment to X7; The X7 is [ka] wherein: R NX7 is H, C1-C6 alkyl or C1-C6 haloalkyl; Ring A7 is aryl or heteroaryl; R X7 are each independently a halogen, -CN, -NO2, -OH, or -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; wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally and independently selected from one or more R XA is replaced by; kx7 is 0, 1, 2 or 3; mx7 is 0, 1, 2, 3, 4 or 5; * X6 indicates the point of attachment to X6; * X8 indicates the point of attachment to X8; X8 is an L-amino acid having an -H on the α-amino group; X9 is [ka] wherein: R NX9 is H, C1-C6 alkyl or C1-C6 haloalkyl; Ring A9 is aryl or heteroaryl; R X9 are each independently a halogen, -CN, -NO2, -OH, or -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 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally and independently selected from one or more R XA is replaced by; kx9 is 0, 1, 2 or 3; mx9 is 0, 1, 2, 3, 4, or 5; * X8 indicates the point of attachment to X8; * XC represents (i) the point of attachment to X10 or (i) X12 if X10 and X11 are absent; X10 is absent or an L-amino acid; X11 is absent or is an L-amino acid; with the proviso that if X10 is absent, then X11 is also absent; X12 is an L-amino acid with 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, 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 b 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, 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 dare 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; or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; 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 connecting the peptide to the payload molecule. A linkered peptide or conjugate comprising:

[0213] 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.

[0214] In some embodiments, X7 is W1Me, Na11, Na12, W1Et, Na121N, 3Bzf, 3Bzt, Na115N, Na114N, Na124N, Na128N, F23dMe, F23dC, W1Me7N, or W1Me7Cl. In some embodiments, X7 is W1Me, F23dMe, or W1Me7Cl.

[0215] In some embodiments, X9 is [ka] and each R X9 are independently selected from —OH, CN, NH2, C1-C3 alkyl, —Cl, —F, —Br, —CONH2, and —SO2F.

[0216] In some embodiments, [ka] teeth, [ka] is.

[0217] In some embodiments, R X9 each of which is independently selected from halogen, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -SH, -SR a , -S(=O)Ra , -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.

[0218] In some embodiments, X9 is W1Me, W, Na11, W1Et, Na121N, 3Bzf, 3Bzt, Na114N, Na118N, F23dMe, F23dC, or W1Et. In some embodiments, X9 is W1Me or F23dMe.

[0219] In some embodiments, ring A2 is a 6-membered heteroaryl containing 1 or 2 N.

[0220] 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 It is alkyl.

[0221] In some embodiments, X7 is W1Me, W1MeCl, W1MeBr, Na1, Na12, W1Et, 3Bzf, 3Bzt, F23dC, W1Me7N, or F23dMe; X8 is V, KCOpipzaa, Hse, N, Cit, hCit, KAc, DapAc, OrnAc, T, alT, Aib, Alb, Qglucamine, Hgl, E, Hgn, MeF, 3Py6NH2, W1Me, A, Q, or K; and X9 is W1Me, Na1, W1Et, Na121N, 3Bzf, 3Bzt, Na118N, F23dMe, or F23dC.

[0222] In some embodiments, X7 is W1Me; X8 is V; and X9 is W1Me.

[0223] In some embodiments of Formula (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., a D-amino acid). In some embodiments, X1 is any one of the standard amino acids. In some embodiments, X1 is an unnatural 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-5F. In some embodiments, a payload molecule or a linker is attached to X1.

[0224] 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., a 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.

[0225] In some embodiments of Formula (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 an unnatural amino acid. In some embodiments, X2 is an aromatic amino acid or variant thereof. In some embodiments, X2 is V. In some embodiments, X2 is an N-methylated amino acid or variant thereof. In some embodiments, X2 is an N-alkylated amino acid or variant thereof. In some embodiments, X2 is an amino acid comprising an aryl group. In some embodiments, X2 is an amino acid comprising an optionally substituted phenyl group. In some embodiments, X2 is an amino acid comprising an optionally substituted naphthyl group. In some embodiments, X2 is an amino acid comprising a heteroaryl group. In some embodiments, X2 is an amino acid comprising an optionally substituted monocyclic heteroaryl group. In some embodiments, X2 is an amino acid comprising an optionally substituted bicyclic heteroaryl group. In some embodiments, the aryl or heteroaryl is optionally substituted with one, two, or three substituents independently selected from -CH3, -ethyl, -Cl, and -F. In some embodiments, the aryl or heteroaryl is optionally substituted with one, two, or three substituents independently selected from -OH, oxo, halogen, CN, amino, C1-C6 alkyl, C1-C6 alkoxyl, and C1-C6 haloalkyl. In some embodiments, X2 is F, or an unsubstituted phenyl ring of F is (i) substituted with -OH, -CN, -C 1~3 (ii) a phenyl ring substituted with one or two substituents each independently selected from alkyl, —OH, —CN, —C 1~3and variants thereof substituted with a 6-membered heteroaryl ring optionally substituted with one or two substituents each independently selected from alkyl, wherein F or structural variants thereof are optionally N-methylated. In some embodiments, X2 is Me3Py. 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. In some embodiments, X2 is histidine (H). In some embodiments, X2 is phenylalanine, tryptophan, tyrosine, or variants thereof. In some embodiments, X2 is phenylalanine or variants 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, a payload molecule or a linker is attached to X2. In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (Ia), (Ib), (Ic), and (III-2), X2 is an amino acid comprising an aromatic ring or an N-methylated amino acid thereof. In some embodiments, X2 is an N-methylated amino acid. In some embodiments, X2 is an amino acid comprising an aromatic ring. In some embodiments, X2 is an N-methylated amino acid comprising an aromatic ring. In some embodiments, X2 is F or a variant thereof, Y or a variant thereof, W or a variant thereof, or an 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).

[0226] In some embodiments of Formula (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 an unnatural amino acid. In some embodiments, X3 is asparagine (N). In some embodiments, X3 is an alternative to asparagine. In some embodiments, X3 is absent. In some embodiments of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (Ia), and (III-2), X3 is absent. In some embodiments of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (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 comprising an -OH, -NH2, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)C(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 is , 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 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. In some embodiments, X3 is an amino acid comprising a charged side chain. In some embodiments, X3 is an amino acid comprising 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 comprises an —OH, —COOH, —NH—, or NH2 moiety.In some embodiments, X3 comprises -OH, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3. In some embodiments, X3 comprises 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-CC 1~6In some embodiments, X3 is absent, a hydrophilic amino acid (e.g., 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-glucamine). 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, RX3 is Ala. In some embodiments, RX3 is da. In some embodiments, X3 is absent.In some embodiments, a payload molecule or linker is attached to X. In some embodiments, X is attached directly to X.

[0227] 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 hydrophobic amino acid or variant thereof. In some embodiments, X4 is an unnatural amino acid. In some embodiments, X4 is a standard amino acid. In some embodiments, X4 is leucine. In some embodiments, X4 comprises four or more carbon atoms in its side chain, which may comprise a linear, branched, or cyclic carbon chain. In some embodiments, X4 comprises four or more consecutive carbon atoms in its side chain. In some embodiments, X4 comprises an ethylene, propylene, or butylene group in its 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), or alternatives thereof. 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 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). In some embodiments, X4 is an amino acid comprising a hydrophobic side chain. In some embodiments, X4 is an amino acid comprising 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, a straight or branched chain C 1~5 Alkyl-substituted G, C 3~7In some embodiments, X4 is A substituted with cycloalkyl, 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 a straight or branched chain C 1~5 In some embodiments, X4 is G substituted with alkyl. In some embodiments, X4 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, or isopentyl. In some embodiments, X4 is C 3~7X4 is A substituted with cycloalkyl. In some embodiments, X4 is A substituted with cyclopropyl. In some embodiments, X4 is A substituted with cyclobutyl. In some embodiments, X4 is A substituted with cyclopentyl. In some embodiments, X4 is A substituted with cyclohexyl. In some embodiments, X4 is A substituted with cycloheptyl. 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 a linker is attached to X4. In some embodiments, X1 is directly attached 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 comprising an -OH, -NH2, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)C(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 comprises an -OH, -COOH, -NH-, or NH2 moiety. In some embodiments, X4 comprises an -OH, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3. In some embodiments, X4 comprises a C1-C6 hydroxyalkyl, a C1-C6 aminoalkyl, -C. 0~6 Alkylene-NH-C(=NH)-NH2, -C 0~6 Alkylene-CO-NH2, -C 0~6 Alkylene -COOH or -NH-CC 1~6 Contains alkyl side chains.

[0228] 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 hydrophobic amino acid. In some embodiments, X4 comprises at least four consecutive carbon atoms, either straight or branched. In some embodiments, X4 comprises at least five consecutive carbon atoms, either straight 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.

[0229] In some embodiments of Formula (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 variant thereof. In some embodiments, X5 is a hydrophilic amino acid. In some embodiments, X5 is an unnatural 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 such as da and mutations such as Q glucamine). In some embodiments, X5 is Hgn, N, Q glucamine, 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 glucamine. 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 Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (III-1), and (III-2), 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). In some embodiments, X5 is an amino acid comprising a charged side chain. In some embodiments, X5 is an amino acid comprising a polar, uncharged side chain.In some embodiments of Formula (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), where hydrophilic amino acids include L-amino acids including -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 comprising -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 comprising -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 attached directly to X5.

[0230] In some embodiments of Formula (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 an unnatural 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 substitute thereof. In some embodiments, X6 is an amino acid having an aromatic ring or a substitute thereof. In some embodiments, X6 is an amino acid comprising an aryl group. 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 naphthyl group. In some embodiments, X6 is an amino acid comprising a heteroaryl group. In some embodiments, X6 is an amino acid comprising an optionally substituted monocyclic heteroaryl group. In some embodiments, X6 is an amino acid comprising an optionally substituted bicyclic heteroaryl group. In some embodiments, the aryl or heteroaryl is optionally substituted with one, two, or three substituents independently selected from -CH3, -ethyl, -Cl, and -F. In some embodiments, the aryl or heteroaryl is optionally substituted with one, two, or three substituents independently selected from -OH, oxo, halogen, CN, amino, C1-C6 alkyl, C1-C6 alkoxyl, and C1-C6 haloalkyl. In some embodiments, X6 is an N-methylated amino acid. In some embodiments, X6 is a hydrophilic amino acid or its substitute. In some embodiments, X6 is an amino acid or its substitute having an aromatic ring. In some embodiments, X6 is an N-methylated amino acid or its substitute. In some embodiments, X6 is MeN. 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 glucamine. In some embodiments, X6 is MeF4C. In some embodiments, X6 is absent.In some embodiments of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ic), (III-1), and (III-2), 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). In some embodiments, X6 is an amino acid comprising a charged side chain. In some embodiments, X6 is an amino acid comprising a polar, uncharged side chain. In some embodiments of Formula (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 comprising an aromatic ring, or an N-methylated amino acid thereof. In some embodiments of Formula (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 containing an -OH, -NH2, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)C(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 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-CC 1~6In some embodiments, 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, 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 an N-methylated amino acid thereof. 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 an N-methylated amino acid thereof. In some embodiments, X6 is an amino acid comprising an optionally substituted phenyl. In some embodiments, X6 is an amino acid comprising an optionally substituted heteroaryl. In some embodiments, X6 is F or a variant thereof, or an N-methylated amino acid thereof. 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 a variant thereof, or an N-methylated amino acid thereof. In some embodiments, X6 is Y or MeY. In some embodiments, X6 is Y. In some embodiments, X6 is MeY. In some embodiments, a payload molecule or linker is attached to X6.In some embodiments, X1 is directly bonded to X6.

[0231] 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 an unnatural 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 substitute thereof. In some embodiments, X7 is an amino acid comprising an aryl group. In some embodiments, X7 is an amino acid comprising an optionally substituted phenyl group. In some embodiments, X7 is an amino acid comprising an optionally substituted naphthyl group. In some embodiments, X7 is an amino acid comprising a heteroaryl group. In some embodiments, X7 is an amino acid comprising an optionally substituted monocyclic heteroaryl group. In some embodiments, X7 is an amino acid comprising an optionally substituted bicyclic heteroaryl group. In some embodiments, the aryl or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from -CH3, -ethyl, -Cl, and -F. In some embodiments, the aryl or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from -OH, oxo, halogen, CN, amino, C1-C6 alkyl, C1-C6 alkoxyl, and C1-C6 haloalkyl. In some embodiments, X7 is W, Y, or a variant thereof (such as an amino acid having either a 6-membered aryl or heteroaryl, or a 9- or 10-membered bicyclic aryl or heteroaryl bonded to the alpha carbon through a carbon (e.g., a methylene group), where the 6-, 9-, and 10-membered heteroaryl have one heteroatom (e.g., N), and the 6-, 9-, and 10-membered aryl or heteroaryl is optionally substituted with one or two substituents independently 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 comprising an aromatic ring. In some embodiments, X7 is an amino acid comprising 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 Na11, Na12, W1Et, Na121N, 3Bzf, 3Bzt, Na15N, Na14N, Na124N, Na128N, 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, Na11, Na12, W1Et, Na121N, 3Bzf, 3Bzt, Na15N, Na14N, Na124N, Na128N, 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, a payload molecule or linker is attached to X7. In some embodiments, X1 is attached directly to X7.

[0232] In some embodiments of Formulas (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 one of the standard amino acids. In some embodiments, X8 is an unnatural amino acid. In some embodiments, X8 is V, a hydrophilic amino acid, an N-methylated amino acid, or a substitute 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 variant thereof. In some embodiments, X8 is an N-alkylated amino acid or a substitute 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 glucamine. In some embodiments, X8 is Cit. In some embodiments, X8 is hCit. In some embodiments, X8 is absent. In some embodiments of Formulas (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 with a functional side chain. In some embodiments; X8 is one or two straight or branched chain C 1~5 Alkyl-substituted G, C 3~7and A substituted with a cycloalkyl or A substituted with a hydrophilic amino acid, where the hydrophilic amino acid comprises an L-amino acid containing -NH, one or more of -OH, -C(O)OH, -NHC(NH)NH, -NHC(O)NH, -C(O)NH, -NHC(O)CH; or the hydrophilic amino acid comprises a zwitterion. In some embodiments, X is V, A, E, N, K, Q Glucamine, KCOpipzaa, Q, Hse, N, Cit, Hcit, Kac, DapAc, OrnAc, T, a1T, Aib, Alb, or 3Py6NH. In some embodiments, X is A, E, N, K, Q Glucamine, KCOpipzaa, Q, Hse, N, Cit, Hcit, Kac, DapAc, OrnAc, T, a1T, Aib, Alb, or 3Py6NH. In some embodiments, X8 is KCOpipzaa, N, Cit, Q Glucamine, hCit, K, KAc, Aib, Alb, DapAc, OrnAc, A, T, a1T, norleucine, norvaline, Hgl, E, Hgn, Q, I, or L. In certain embodiments, X8 is KCOpipzaa, V, Q Glucamine, Cit, Hcit, K, or 3Py6NH2. In certain embodiments, X8 is KCOpipzaa, Q Glucamine, Cit, Hcit, K, or 3Py6NH2. In some embodiments, X8 is V, KCOpipzaa, Cit, Q Glucamine, hCit, Aib, Alb, norleucine, or norvaline. In some embodiments, X8 is KCOpipzaa, Cit, Q Glucamine, hCit, Aib, Alb, norleucine, or norvaline. In some embodiments, X8 is KCOpipzaa, N, Cit, hCit, KAc, DapAc, OrnAc, A, T, a1T, Aib, Alb, Qglucamine, Hgl, Q, E, Hgn, or K. In some embodiments, X8 is a hydrophobic amino acid. In some embodiments, X8 is a straight or branched chain C 1~5 In some embodiments, X8 is G substituted with one or more substituents selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and isopentyl. In some embodiments, X8 is C 3~7X8 is A substituted with cycloalkyl. 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 comprising -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 comprising -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 comprising a 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-glucamine. In some embodiments, a payload molecule or a linker is attached to X8. In some embodiments, X1 is attached directly to X8.

[0233] In some embodiments of Formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (III-1), and (III-2), X is W or a variant thereof. In some embodiments, X is a standard amino acid. In some embodiments, X is an unnatural amino acid. In some embodiments, X is WMe, WMeCl, FdMe, NaI, NaI, WIEt, NaI N, 3Bzf, 3Bzt, NaI N, NaI N, NaI N, NaI N, FdC, or WMeN. In some embodiments, X is WMe or FdMe. In some embodiments, X is WMe. In some embodiments, X is WMeCl. 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 substitute 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 comprising an aromatic ring. In some embodiments, X9 is an amino acid comprising an aryl group. In some embodiments, X9 is an amino acid comprising an optionally substituted phenyl group. In some embodiments, X9 is an amino acid comprising an optionally substituted naphthyl group. In some embodiments, X9 is an amino acid comprising a heteroaryl group. In some embodiments, X9 is an amino acid comprising an optionally substituted monocyclic heteroaryl group. In some embodiments, X9 is an amino acid comprising an optionally substituted bicyclic heteroaryl group. In some embodiments, the aryl or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from -CH, -ethyl, -Cl, and -F. In some embodiments, the aryl or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from -OH, oxo, halogen, CN, amino, C1-C6 alkyl, C1-C6 alkoxyl, and C1-C6 haloalkyl.In some embodiments, X is W, Y, or a variant thereof (such as an amino acid having either a 6-membered aryl or heteroaryl, or a 9- or 10-membered bicyclic aryl or heteroaryl bonded to the alpha carbon through a carbon (e.g., a methylene group), where the 6-, 9-, and 10-membered heteroaryl have one heteroatom (e.g., N), and the 6-, 9-, and 10-membered aryl or heteroaryl is optionally substituted with one or two substituents independently selected from -CH, -ethyl, -Cl, and -F). In some embodiments, X is an amino acid containing an aromatic ring (e.g., W or a variant thereof). In some embodiments, X is F or a variant thereof, or W or a variant thereof. In some embodiments, X is WMe, WMeCl, WMeN, FdMe, WEt, WMe, W, F, or 7-AzaTrp. In some embodiments, X 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 a linker is attached to X9. In some embodiments, X1 is attached directly to X9.

[0234] In some embodiments of Formulas (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 an unnatural amino acid. In some embodiments, X10 is threonine (T). In some embodiments, X10 is absent. In some embodiments of Formulas (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, T, or a variant thereof, is a straight or branched C 1~5 X is an L-amino acid optionally substituted with alkyl, K or a variant thereof, Cit or a variant thereof, or -NHC(NH)NH, -NHC(O)NH, -C(O)NH, or -NHC(O)CH. In some embodiments, X is absent, T, Q, S, Hgn, alpha-methylserine, hSer, hThr, N, OrnAc, LysAc, Cit, or hCit. In some embodiments, X is absent. In some embodiments, X is a polar amino acid. In some embodiments, X is Q. In some embodiments, X is Hgn. In some embodiments, X is S or a variant thereof. In some embodiments, X is S, alpha-methylserine, or hSer. In some embodiments, X is S. In some embodiments, X is alpha-methylserine. In some embodiments, X is hSer. In some embodiments, X10 is a straight or branched chain C 1~5X10 is T or a variant thereof optionally substituted with alkyl. 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 a linker is attached to X10. In some embodiments, X1 is directly attached to X10.

[0235] 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 substitute thereof. In some embodiments, X11 is serine, threonine, tyrosine, asparagine, or glutamine, or a substitute thereof. In some embodiments, X11 is a standard amino acid. In some embodiments, X11 is an unnatural 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 Formula (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 with 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), X 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, X is an amino acid comprising a charged side chain. In some embodiments, X is an amino acid comprising a polar, uncharged side chain. In some embodiments, X is an amino acid comprising an -OH, -NH, -C(O)OH, -NHC(=NH)NH, -NHC(O)NH, -C(O)NH, or -NHC(O)C(O)CH 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 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-CC 1~6In some embodiments, X is absent, E, Hgn, R or a variant thereof, Cit or a variant thereof, Hgl, K or a variant thereof, D, N, or Q. In some embodiments, X is absent, E, Hgn, R, hArg, Cit, hCit, Hgl, Orn, D, N, Q, DapAc, OrnAc, DabAc, or norCit. In some embodiments, X is absent, arginine (R), asparagine (N), aspartic acid (D), glutamine (Q), lysine (K), or a non-natural hydrophilic amino acid. In some embodiments, X is absent, Hgn, R, hArg, Cit, hCit, Hgl, Orn, D, N, Q, DapAc, OrnAc, DabAc, or norCit. In some embodiments, X is Hgn, R, hArg, Cit, hCit, Hgl, Orn, D, N, Q, DapAc, OrnAc, DabAc, or norCit. In some embodiments, X is 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-glucamine). In some embodiments, X is Q, K, G, S, T, 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-glucamine). 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 a variant thereof. 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 a variant thereof. 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 a variant thereof. 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 a linker is attached to X11. In some embodiments, X1 is directly attached to X11.

[0236] In some embodiments of Formula (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 an unnatural amino acid. In some embodiments, X12 is cysteine. In some embodiments, X12 is a substitute for 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 Formula (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 attached to X12.

[0237] In some embodiments, the peptide or pharmaceutically acceptable salt thereof has a cyclic structure, and the first amino acid (or X1) is covalently linked to the last amino acid (or X12).

[0238] In some embodiments, the peptide or pharmaceutically acceptable salt thereof has a cyclic structure with an amino acid (e.g., a chloroacetylated amino acid) and a cysteine ​​residue or variant thereof at the first residue, X1, wherein the amino acid (e.g., a chloroacetylated amino acid) and the cysteine ​​residue or variant thereof in X1 form a covalent bond.

[0239] In some embodiments, the peptide has a monocyclic structure. In certain embodiments, the amino acid X1 and cysteine ​​or a variant thereof form a covalent bond.

[0240] In some embodiments, the peptide of Formula (I) has the structure of Formula (I-1), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R 1 is selected from the group consisting of NH2 and OH; R 2 is H or C 1~3 selected from the group consisting of alkyl; R 3 is H or C 1~3 selected from the group consisting of alkyl; The points of attachment to the payload molecule or linker are not indicated; X1 to X11 are described in formula (I).

[0241] In some embodiments, the peptide of formula (I-1) has the structure of formula (I-2), or a pharmaceutically acceptable salt thereof: [ka]

[0242] In some embodiments, the peptide of formula (I-1) has the structure of formula (I-3), or a pharmaceutically acceptable salt thereof: [ka]

[0243] In some embodiments, the peptide of formula (I-1) has the structure of formula (I-4), or a pharmaceutically acceptable salt thereof: [ka]

[0244] In some embodiments of formula (I-1), (I-2), (I-3), or (I-4), R 1 In some embodiments of formula (I-1), (I-2), (I-3), or (I-4), R 1 is NH2.

[0245] 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 In some embodiments of formula (I-1), (I-2), (I-3), or (I-4), R 2 is methyl.

[0246] 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 In some embodiments of formula (I-1), (I-2), (I-3), or (I-4), R 3 is methyl.

[0247] In some embodiments, the peptide of Formula (I) has the structure of Formula (I-5), or a pharmaceutically acceptable salt thereof: [ka] In the formula, X1 to X12 have the above definitions, and Lcyc is a ring-closing group that covalently bonds X1 to X12.

[0248] In some embodiments, Lcyc is a group selected from Table 4B. In some embodiments, Lcyc is formed by reacting a first and second functional group in Table 4C.

[0249] 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) During the ceremony, 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; X3 is N or a variant thereof; X4 is any hydrophobic amino acid or 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 variant thereof; X9 is W or a variant thereof; X10 is T or a variant thereof; X11 is any hydrophilic amino acid; X12 is C or a variant thereof, a peptide of formula (I), or a pharmaceutically acceptable salt thereof.

[0250] In some embodiments of Formula (I), X1 is a D-amino acid (such as da, df3CON, dahp, or dkCOpipzaa); X2 is N-methylated phenylalanine or a variant thereof (such as Me3Py, MeF, MeF3H, or MeF3CN); X3 is N; X4 is a hydrophobic amino acid or an N-methylated amino acid (such as leucine, Cbg, or Chg); X5 is Hgn, asparagine (N), 2,4-diaminobutyric acid (Dab), Q glucamine, KCOpipzaa, Hgl, Nmm, Ndm, or lysine (K); X6 is asparagine (N) or N-methylated glutamic acid (E), N-methylated asparagine, N-methylated phenylalanine (F) or a substitute thereof (such as Q-glucamine, MeE, MeN, Me3Py, MeF, MeF4C, or N); X7 is W1Me, W1Me7Cl, or W1Me7N; X8 is KCOpipzaa, V, Qglucamine, 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, glutamic acid (E), lysine (K); X12 is a cysteine.

[0251] In some embodiments, the amino acid of Formula (I) has a sequence of Formula (Ia), or a pharmaceutically acceptable salt thereof. X1-X2-X3-X4-X5-X6-X7-X8-X9-X12 Formula (Ia).

[0252] In some embodiments, the amino acid of Formula (I) has a sequence of Formula (Ib), or a pharmaceutically acceptable salt thereof. X1-X2-X4-X5-X7-X8-X9-X12 Formula (Ib).

[0253] In some embodiments, the amino acid of Formula (I) has a sequence of Formula (Ic), or a pharmaceutically acceptable salt thereof. X1-X2-X6-X7-X8-X9-X12 Formula (Ic).

[0254] In some embodiments, the peptides described herein have 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) During the ceremony, 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; X3 is N or a variant thereof; X4 is any hydrophobic amino acid or 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 variant thereof; X9 is W or a variant thereof; X12 is C or a variant thereof.

[0255] In some embodiments, the peptides described herein have an amino acid sequence set forth in Formula (Ib), or a pharmaceutically acceptable salt thereof: X1-X2-X4-X5-X7-X8-X9-X12 Formula (Ib) (In the formula, 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 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; X12 is C or a variant thereof.

[0256] 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) During the ceremony, 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; X12 is C or a variant thereof.

[0257] In some embodiments, the peptide of Formula (I), (Ia), (Ib), and / or (Ic) is monocyclic. In some embodiments, the amino acid in X1 and the cysteine ​​or cysteine ​​substitution are conjugated.

[0258] In some embodiments, the peptide or 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 that has up to 1, 2, 3, 4, or 5 substitutions with conservative variants compared to any one of the sequences selected from SEQ ID NOs: 1-171.

[0259] In some embodiments, the peptide or salt thereof consists of an amino acid sequence selected from SEQ ID NOs: 1-171.

[0260] In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 1-122, 159-163, and 165-171, wherein the peptide has a cyclic structure with a cysteine ​​residue or a variant thereof at residue 12, and the amino acid at X1 (e.g., a chloroacetylated amino acid) and the cysteine ​​residue or a variant thereof at residue 12 form a covalent bond (e.g., by reacting the chloroacetyl group in the amino acid at X1 with the cysteine ​​residue or a variant thereof).

[0261] In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 123-149 and 164, wherein the peptide has a cyclic structure with a cysteine ​​residue or variant thereof at the tenth residue, and the amino acid at X1 (e.g., a chloroacetylated amino acid) and the cysteine ​​residue or variant thereof at the tenth residue form a covalent bond.

[0262] In some embodiments, the peptide exhibits a K d As determined by HPLC, the antibody has a binding affinity for human EphA2 of 100 nM or less.

[0263] In some embodiments, the peptide exhibits a K d As determined by HPLC, the antibody has a binding affinity for human EphA2 of 1 nM or less.

[0264] In some embodiments, peptides of the present disclosure bind to the ligand binding domain (LBD) of human EphA2.

[0265] In some embodiments, a peptide of the disclosure makes good contact with Asp53 and / or Glu157 of human EphA2 represented by SEQ ID NO: 276. In some embodiments, a peptide of the disclosure interacts with Asp53 and / or Glu157 of human EphA2 represented by SEQ ID NO: 276. In some embodiments, a peptide of the disclosure interacts with Asp53 and / or Glu157 of human EphA2 represented by 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.

[0266] In some embodiments, peptides of the present disclosure interact with human EphA2 at one or more residues selected from Asp53, Met55, Asn57, Met59, Met66, Thr101, Arg103, Phe156, Glu157, Arg159, Val161, Val189, and Ala190. In some embodiments, peptides of the present disclosure bind to Asp53 and Glu157 of human EphA2. In some embodiments, amino acid residue X5 of Formula (I) interacts with Glu157 of human EphA2. In some embodiments, amino acid residue X6 of Formula (I) interacts with Arg159 of human EphA2. In some embodiments, 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, amino acid residue X9 of Formula (I) interacts with one or more of Phe156, Arg103, and Val189. In some embodiments, amino acid residue X11 of Formula (I) interacts with Asp53 of human EphA2. In some embodiments, amino acid residue X7 of Formula (I) forms a π-π stacking interaction with Phe156 of human EphA2. In some embodiments, amino acid residue X9 of Formula (I) forms a π-π stacking interaction with Phe156 of human EphA2. In some embodiments, amino acid residue X2 of Formula (I) interacts with the backbone carbonyl of C70 of human EphA2 protein via an intermolecular aromatic H-bonding interaction.

[0267] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide is bound to human EphA2, amino acid residue X2 of Formula (I) is located less than 15 Å from C70 of human EphA2. In some embodiments, X2 is located less than 10 Å from C70. In some embodiments, X2 is located less than 6 Å from C70. In some embodiments, X2 is located less than 4 Å from C70.

[0268] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide is bound to human EphA2, amino acid residue X7 of Formula (I) is located less than 10 Å from Phe156 of human EphA2. In some embodiments, X7 is located less than 6 Å from Phe156. In some embodiments, X7 is located less than 4 Å from Phe156.

[0269] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide is bound to human EphA2, amino acid residue X7 of Formula (I) is located less than 20 Å from Thr101 of human EphA2. In some embodiments, X7 is located less than 15 Å from Thr101. In some embodiments, X7 is located less than 10 Å from Thr101. In some embodiments, X7 is located less than 6 Å from Thr101. In some embodiments, X7 is located less than 4 Å from Thr101.

[0270] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide is bound to human EphA2, amino acid residue X7 of Formula (I) is located less than 20 Å from Asn57 of human EphA2. In some embodiments, X7 is located less than 15 Å from Asn57. In some embodiments, X7 is located less than 10 Å from Asn57. In some embodiments, X7 is located less than 6 Å from Asn57. In some embodiments, X7 is located less than 4 Å from Asn57.

[0271] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide is bound to human EphA2, amino acid residue X7 of Formula (I) is located less than 20 Å from Val161 of human EphA2. In some embodiments, X7 is located less than 15 Å from Val161. In some embodiments, X7 is located less than 10 Å from Val161. In some embodiments, X7 is located less than 6 Å from Val161. In some embodiments, X7 is located less than 4 Å from Val161.

[0272] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide is bound to human EphA2, amino acid residue X7 of Formula (I) is located less than 20 Å from Met59 of human EphA2. In some embodiments, X7 is located less than 15 Å from Met59. In some embodiments, X7 is located less than 10 Å from Met59. In some embodiments, X7 is located less than 6 Å from Met59. In some embodiments, X7 is located less than 4 Å from Met59.

[0273] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide is bound to human EphA2, amino acid residue X7 of Formula (I) is located less than 20 Å from Ala190 of human EphA2. In some embodiments, X7 is located less than 15 Å from Ala190. In some embodiments, X7 is located less than 10 Å from Ala190. In some embodiments, X7 is located less than 6 Å from Ala190. In some embodiments, X7 is located less than 4 Å from Ala190.

[0274] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide is bound to human EphA2, amino acid residue X7 of Formula (I) is located less than 20 Å from Met66 of human EphA2. In some embodiments, X7 is located less than 15 Å from Met66. In some embodiments, X7 is located less than 10 Å from Met66. In some embodiments, X7 is located less than 6 Å from Met66. In some embodiments, X7 is located less than 4 Å from Met66.

[0275] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide is bound to human EphA2, amino acid residue X9 of Formula (I) is located less than 10 Å from Phe156 of human EphA2. In some embodiments, X9 is located less than 6 Å from Phe156. In some embodiments, X9 is located less than 4 Å from Phe156.

[0276] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide is bound to human EphA2, amino acid residue X9 of Formula (I) is located less than 15 Å from Asn3 of human EphA2. In some embodiments, X9 is located less than 10 Å from Asn3. In some embodiments, X9 is located less than 6 Å from Asn3. In some embodiments, X9 is located less than 4 Å from Asn3.

[0277] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide is bound to human EphA2, amino acid residue X9 of Formula (I) is located less than 15 Å from Arg103 of human EphA2. In some embodiments, X9 is located less than 10 Å from Arg103. In some embodiments, X9 is located less than 6 Å from Arg103. In some embodiments, X9 is located less than 4 Å from Arg103.

[0278] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide is bound to human EphA2, amino acid residue X9 of Formula (I) is located less than 15 Å from Val189 of human EphA2. In some embodiments, X9 is located less than 10 Å from Val189. In some embodiments, X9 is located less than 6 Å from Val189. In some embodiments, X9 is located less than 4 Å from Val189.

[0279] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide is bound to human EphA2, amino acid residue X8 of Formula (I) is located less than 10 Å from Phe156 of human EphA2. In some embodiments, X8 is located less than 6 Å from Phe156. In some embodiments, X8 is located less than 4 Å from Phe156.

[0280] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide is bound to human EphA2, amino acid residue X2 of Formula (I) is located less than 15 Å from C70 of human EphA2. In some embodiments, X2 is located less than 10 Å from C70. In some embodiments, X2 is located less than 7 Å from C70. In some embodiments, X2 is located less than 4 Å from C70.

[0281] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide is bound to human EphA2, amino acid residue X7 of Formula (I) is located less than 10 Å from Phe156 of human EphA2. In some embodiments, X7 is located less than 6 Å from Phe156. In some embodiments, X7 is located less than 3 Å from Phe156.

[0282] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide is bound to human EphA2, amino acid residue X9 of Formula (I) is located less than 20 Å from Thr101 of human EphA2. In some embodiments, X9 is located less than 15 Å from Thr101. In some embodiments, X9 is located less than 10 Å from Thr101. In some embodiments, X9 is located less than 6 Å from Thr101. In some embodiments, X9 is located less than 5 Å from Thr101.

[0283] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide is bound to human EphA2, amino acid residue X8 of Formula (I) is located less than 20 Å from Asn57 of human EphA2. In some embodiments, X8 is located less than 15 Å from Asn57. In some embodiments, X8 is located less than 10 Å from Asn57. In some embodiments, X8 is located less than 6 Å from Asn57. In some embodiments, X8 is located less than 4 Å from Asn57.

[0284] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide is bound to human EphA2, amino acid residue X7 of Formula (I) is located less than 20 Å from Val161 of human EphA2. In some embodiments, X7 is located less than 15 Å from Val161. In some embodiments, X7 is located less than 11 Å from Val161. In some embodiments, X7 is located less than 6 Å from Val161. In some embodiments, X7 is located less than 5 Å from Val161.

[0285] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide is bound to human EphA2, amino acid residue X7 of Formula (I) is located less than 20 Å from Met59 of human EphA2. In some embodiments, X7 is located less than 15 Å from Met59. In some embodiments, X7 is located less than 11 Å from Met59. In some embodiments, X7 is located less than 6 Å from Met59. In some embodiments, X7 is located less than 4 Å from Met59.

[0286] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide is bound to human EphA2, amino acid residue X7 of Formula (I) is located less than 20 Å from Ala190 of human EphA2. In some embodiments, X7 is located less than 15 Å from Ala190. In some embodiments, X7 is located less than 11 Å from Ala190. In some embodiments, X7 is located less than 6 Å from Ala190. In some embodiments, X7 is located less than 4 Å from Ala190.

[0287] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide is bound to human EphA2, amino acid residue X7 of Formula (I) is located less than 20 Å from Met66 of human EphA2. In some embodiments, X7 is located less than 15 Å from Met66. In some embodiments, X7 is located less than 10 Å from Met66. In some embodiments, X7 is located less than 6 Å from Met66. In some embodiments, X7 is located less than 4 Å from Met66.

[0288] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide is bound to human EphA2, amino acid residue X2 of Formula (I) is located less than 15 Å from Arg103 of human EphA2. In some embodiments, X2 is located less than 10 Å from Arg103. In some embodiments, X2 is located less than 6 Å from Arg103. In some embodiments, X2 is located less than 4 Å from Arg103.

[0289] In some embodiments, when a peptide of Formula (I) or a conjugate comprising the peptide is bound to human EphA2, amino acid residue X9 of Formula (I) is located less than 15 Å from Val189 of human EphA2. In some embodiments, X9 is located less than 10 Å from Val189. In some embodiments, X9 is located less than 6 Å from Val189. In some embodiments, X9 is located less than 4 Å from Val189.

[0290] In certain embodiments, the peptide has a plasma half-life (T) 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. 1 / 2 In certain embodiments, the peptide has a plasma half-life (T) of at least 250 minutes as determined in vitro in human plasma at 37°C. 1 / 2) It has.

[0291] In some embodiments, the conjugate of the present disclosure has the structure of formula (III-1): [ka] In the formula, -linker- represents a linker.

[0292] In some embodiments, the conjugate comprising the cyclic peptide of formula (I) has the structure of formula (III-2): [ka] During the ceremony, X1 to X12 have the above definitions, and Lcyc is a ring-closing group that covalently bonds X1 to X12; -Linker- represents a linker.

[0293] In some embodiments, Lcyc is a group selected from Table 4B. In some embodiments, Lcyc is formed by reacting a first and second functional group in Table 4C. In some embodiments, Lcyc is -C(=O)-CH2-. In some embodiments, Lcyc is -C(=O)-CH2-, which is formed by reacting a chloroacetylated (or bromoacetylated) amino acid with cysteine. In some embodiments, Lcyc is -C(=O)-CH2-S-, which is formed by reacting a chloroacetylated (or bromoacetylated) amino acid with an amino acid containing an SH group.

[0294] In some embodiments, a peptide or pharmaceutically acceptable salt thereof disclosed herein has a cyclic structure having an amino acid (e.g., a chloroacetylated amino acid) at the first residue X1, where the amino acid (e.g., the chloroacetylated amino acid) in X1 and a cysteine ​​residue or variant thereof are bonded. In some embodiments, a peptide or pharmaceutically acceptable salt thereof disclosed herein has a cyclic structure having an amino acid (e.g., a chloroacetylated amino acid) and a cysteine ​​residue or variant thereof at the first residue X1, where the amino acid (e.g., the chloroacetylated amino acid) in X1 and the cysteine ​​residue or variant thereof form a covalent bond. In some embodiments, a peptide or pharmaceutically acceptable salt thereof disclosed herein has a cyclic structure having a bromoacetylated amino acid and a cysteine ​​residue or variant thereof at the first residue X1, where the bromoacetylated amino acid and the cysteine ​​residue or variant thereof in X1 form a covalent bond.

[0295] 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 with a cysteine ​​residue or variant thereof at the twelfth 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 with a cysteine ​​residue or variant thereof at the twelfth residue (X12), and the chloroacetylated amino acid and the cysteine ​​residue or variant thereof at the twelfth residue form a covalent bond. In some embodiments, the chloroacetyl group may be substituted with a bromoacetyl group.

[0296] In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 123-149 and 164, wherein the peptide has a cyclic structure with a cysteine ​​residue or variant thereof at the tenth residue (X10). In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 123-149 and 164, wherein the peptide has a cyclic structure with a cysteine ​​residue or variant thereof at the tenth residue (X10), wherein the amino acid at X1 (e.g., a chloroacetylated amino acid) and the cysteine ​​residue or variant thereof at the tenth residue form a covalent bond. In some embodiments, the chloroacetyl group can be substituted with a bromoacetyl group.

[0297] 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 with a cysteine ​​residue or variant thereof at the eighth 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 with a chloroacetylated amino acid and a cysteine ​​residue or variant thereof at the eighth residue (X8), and the chloroacetylated amino acid and the cysteine ​​residue or variant thereof at the eighth residue form a covalent bond. In some embodiments, the chloroacetyl group can be substituted with a bromoacetyl group.

[0298] In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NO: 158, wherein the peptide has a cyclic structure with a cysteine ​​residue or variant thereof at the seventh residue (X7). In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NO: 158, wherein the peptide has a cyclic structure with a chloroacetylated amino acid and a cysteine ​​residue or variant thereof at the seventh residue (X7), wherein the chloroacetylated amino acid and the cysteine ​​residue or variant thereof at the seventh residue form a covalent bond. In some embodiments, the chloroacetyl group can be substituted with a bromoacetyl group.

[0299] In some embodiments, the peptides disclosed herein, or pharmaceutically acceptable salts thereof, have a cyclic structure in which the first amino acid is covalently linked to the last amino acid.

[0300] In some embodiments, the peptide or pharmaceutically acceptable salt thereof has a cyclic structure with the chloroacetylated amino acid in X1 and a cysteine ​​or substituted cysteine ​​residue, to which the chloroacetylated amino acid in X1 and the cysteine ​​or substituted cysteine ​​are bound. In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 1-171. In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 1-171, and the peptide has a cyclic structure. In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NOs: 1-171, and the peptide has a cyclic structure with the chloroacetylated amino acid and a cysteine ​​or substituted cysteine ​​residue at the C-terminus, to which the chloroacetylated amino acid and the cysteine ​​or substituted cysteine ​​are bound. In some embodiments, the peptide has a cyclic structure having a chloroacetylated amino acid and (i) a cysteine ​​or substituted cysteine ​​residue at residue 12 (where the chloroacetylated amino acid and the cysteine ​​or substituted cysteine ​​at residue 12 are joined); (ii) a cysteine ​​or substituted cysteine ​​residue at residue 10 (where the chloroacetylated amino acid and the cysteine ​​or substituted cysteine ​​at residue 10 are joined). In some embodiments, the chloroacetyl group can be replaced with a bromoacetyl group.

[0301] For example, the cyclic peptide of formula (I) may have the structure shown below: [ka] For example, the cyclic peptide of formula (I) may have the structure shown below: [ka] may have:

[0302] In some embodiments, a conjugate comprising a cyclic peptide of formula (I) has the following structure: [ka] It has.

[0303] In some embodiments, the conjugates of the present disclosure have the structure: [ka] During the ceremony, [ka] represents a linker.

[0304] In some embodiments, the peptide or salt thereof comprises an amino acid sequence that is at least 95% identical to a sequence selected from SEQ ID NOs: (1) X1 to X12 of SEQ ID NOs: 1-122, 159-163, and 165-171, (2) X1 to X10 of SEQ ID NOs: 123-149 and 164, (3) X1 to X8 of SEQ ID NOs: 150-157, and (4) X1 to X7 of SEQ ID NO: 158. In some embodiments, the peptide or salt thereof comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, or 98% identical to a sequence selected from SEQ ID NOs: (1) X1 to X12 of SEQ ID NOs: 1-122, 159-163, and 165-171, (2) X1 to X10 of SEQ ID NOs: 123-149 and 164, (3) X1 to X8 of SEQ ID NOs: 150-157, and (4) X1 to X7 of SEQ ID NO: 158. In some embodiments, the peptide or salt thereof consists of a sequence selected from SEQ ID NOs: (1) X1 to X12 of SEQ ID NOs: 1 to 122, 159 to 163, and 165 to 171, (2) X1 to X10 of SEQ ID NOs: 123 to 149 and 164, (3) X1 to X8 of SEQ ID NOs: 150 to 157, and (4) X1 to X7 of SEQ ID NO: 158. In some embodiments, the peptide or salt thereof comprises an amino acid sequence having 1, 2, 3, 4, or 5 or fewer amino acid residues that differ from a sequence selected from SEQ ID NOs: (1) X1 to X12 of SEQ ID NOs: 1 to 122, 159 to 163, and 165 to 171, (2) X1 to X10 of SEQ ID NOs: 123 to 149 and 164, (3) X1 to X8 of SEQ ID NOs: 150 to 157, and (4) X1 to X7 of SEQ ID NO: 158. In some embodiments, the peptide or salt thereof comprises an amino acid sequence having 1, 2, 3, 4, or 5 or less additions, deletions, and / or substitutions (including conservative substitutions) relative to a sequence selected from SEQ ID NOs: (1) X1 to X12 of SEQ ID NOs: 1 to 122, 159 to 163, and 165 to 171; (2) X1 to X10 of SEQ ID NOs: 123 to 149 and 164; (3) X1 to X8 of SEQ ID NOs: 150 to 157; and (4) X1 to X7 of SEQ ID NO: 158.In some embodiments, the peptide or salt thereof comprises an amino acid sequence having one or less additions, deletions, or substitutions (including conservative substitutions) to a sequence selected from SEQ ID NOs: (1) X1 to X12 of SEQ ID NOs: 1 to 122, 159 to 163, and 165 to 171; (2) X1 to X10 of SEQ ID NOs: 123 to 149 and 164; (3) X1 to X8 of SEQ ID NOs: 150 to 157; and (4) X1 to X7 of SEQ ID NO: 158.

[0305] Exemplary peptides of the present disclosure include those set forth 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 to residue position 1 (e.g., X1). In some embodiments, the peptides in Table 1 have a -C(=O)-CH2-halogen group attached to 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 to residue position 1 (e.g., X1). In some embodiments, the peptides in Table 1 have a -C(=O)-CH2-Cl group attached to residue position 1 (e.g., X1). In some embodiments, the peptides of Table 1 have a -C(=O)-Br group attached to residue position 1 (e.g., X1). In some embodiments, the peptides of Table 1 have a -C(=O)-CH2-Br group attached to residue position 1 (e.g., X1).

[0306] In some embodiments, a conjugate of the present disclosure has a -C(=O)-halogen group attached to the N-terminus. In some embodiments, a conjugate of the present disclosure has a -C(=O)-CH2-halogen group attached to the N-terminus. In some embodiments, a conjugate of the present disclosure has a -C(=O)-halogen group attached to residue position 1 (e.g., X1). In some embodiments, a conjugate of the present disclosure has a -C(=O)-CH2-halogen group attached to residue position 1 (e.g., X1). In some embodiments, a conjugate of the present disclosure has a -C(=O)-Cl group attached to the N-terminus. In some embodiments, a conjugate of the present disclosure has a -C(=O)-CH2-Cl group attached to the N-terminus. In some embodiments, a conjugate of the present disclosure has a -C(=O)-Cl group attached to residue position 1 (e.g., X1). In some embodiments, a conjugate of the present disclosure has a —C(═O)—CH2-Cl group attached to residue position 1 (e.g., X1). In some embodiments, a conjugate of the present disclosure has a —C(═O)—Br group attached to residue position 1 (e.g., X1). In some embodiments, a conjugate of the present disclosure has a —C(═O)—CH2-Br group attached to residue position 1 (e.g., X1). In some embodiments, a peptide in a conjugate of the present disclosure is monocyclic.

[0307] In some embodiments, the peptide of a conjugate described herein is a monocyclic peptide, where —C(═O)—Cl at residue position 1 (e.g., X1) forms a bond with a cysteine ​​at residue position 12 (e.g., X12). In some embodiments, the peptide of a conjugate described herein is a monocyclic peptide, where —C(═O)—CH2-Cl at residue position 1 (e.g., X1) forms a bond with a cysteine ​​at residue position 12 (e.g., X12). In some embodiments, the peptide in a conjugate described herein is a monocyclic peptide with 12 amino acid residues forming a ring.

[0308] In some embodiments, the peptide of the conjugates described herein is a monocyclic peptide, where -C(=O)-Cl at residue position 1 (e.g., X1) forms a bond with a cysteine ​​at residue position 10 (e.g., X10). In some embodiments, the peptide in the conjugates described herein is a monocyclic peptide with 10 amino acid residues forming a ring.

[0309] In one aspect, described herein is a peptide having binding ability to Ephrin type-A receptor 2 (EphA2), wherein the peptide is selected from the group consisting of SEQ ID NO:1: da-MeF-NL-Hgl-MeF-W1Me-V-W1Me-TEC (SEQ ID NO: 1) and a peptide or a pharmaceutically acceptable salt thereof that competes for binding to human EphA2 with a peptide having an amino acid sequence containing one or more amino acid deletions, substitutions, and / or additions in the amino acid sequence of the above.

[0310] In one aspect, described herein is a peptide having binding ability to ephrin type-A receptor 2 (EphA2), wherein the peptide competes for binding to human EphA2 with a peptide having the structure of Formula (I) described herein (e.g., Formulas (I-1) and (I-2)), or a pharmaceutically acceptable salt thereof.

[0311] In some embodiments, the peptides compete for binding to human EphA2 with 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 peptides compete for binding to human EphA2 at one or more amino acid residues selected from Asp53, Phe156, and Glu157. In some embodiments, the peptides compete for binding to human EphA2 at Asp53, Glu157, or both.

[0312] The structures of exemplary unnatural amino acids present in Table 1 can be found in Table 3.

[0313] As set forth in Table 1 or other tables, the abbreviations have the following meanings: Lower case d denotes a D-amino acid, e.g., dF refers to d-phenylalanine; Me refers to a methyl group, e.g., MeG refers to N-methyl-glycine; Ala or A refers to alanine; Arg or R refers to arginine; Asn or N refers to asparagine; Asp or D refers to aspartic acid; Cys or C refers to cysteine; Gln or Q refers to glutamine; Gly or G refers to glycine; His or H refers to histidine; Ile or I refers to isoleucine; Leu or L refers to leucine; Lys or K refers to lysine; Met or M refers to methionine; Phe or F refers to phenylalanine; Pro or P refers to proline; Ser or S refers to serine; Thr or T refers to threonine; Trp or W refers to tryptophan; Tyr or Y refers to tyrosine; Val or V refers to valine; Unless otherwise specified herein, the following abbreviations for unnatural amino acids are used according to the following meanings: Ahp 2-aminoheptanoic acid; Alb 2-amino-3-ureidopropanoic acid, e.g. (S)-2-amino-3-ureidopropanoic acid (CAS no. 1483-07-4); Da or da 2-aminopropanoic acids, such as (2R)-2-aminopropanoic acid; dkCOpipzaa 2-amino-6-{[4-(carboxymethyl)piperazine-1-carbonyl]amino}hexanoic acid, e.g., (2R)-2-amino-6-{[4-(carboxymethyl)piperazine-1-carbonyl]amino}hexanoic acid [ka] Dahp 2-aminoheptanoic acid, e.g. (2R)-2-aminoheptanoic acid [ka] df3CON 2-amino-3-(3-carbamoylphenyl)propanoic acid, e.g. (2R)-2-amino-3-(3-carbamoylphenyl)propanoic acid (CAS number 1217637-40-5) [ka] MeF 2-(methylamino)-3-phenylpropanoic acid, such as (2S)-2-(methylamino)-3-phenylpropanoic acid; Me3Py 2-(methylamino)-3-(pyridin-3-yl)propanoic acid, e.g. (2S)-2-(methylamino)-3-(pyridin-3-yl)propanoic acid (CAS number 1979173-93-7) [ka] Nal1 1-naphthylalanine; 4Py 2-amino-3-(pyridin-4-yl)propanoic acid, e.g. (2S)-2-amino-3-(pyridin-4-yl)propanoic acid (CAS number 169555-95-7) [ka] MeHph 2-(methylamino)-4-phenylbutanoic acid, e.g. (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, for example (2S)-2-amino-3-{1H-pyrrolo[2,3-b]pyridin-3-yl}propanoic acid (CAS number 737007-45-3) [ka] QPh 2-amino-4-(phenylcarbamoyl)butanoic acid, e.g. (2S)-2-amino-4-(phenylcarbamoyl)butanoic acid (CAS no. 198134-12-2); MeF3CN 3-(3-cyanophenyl)-2-(methylamino)propanoic acid, e.g. (2S)-3-(3-cyanophenyl)-2-(methylamino)propanoic acid (CAS number 2642331-80-2) [ka] MeF3H 3-(3-hydroxyphenyl)-2-(methylamino)propanoic acid, e.g. (2S)-3-(3-hydroxyphenyl)-2-(methylamino)propanoic acid [ka] alT 2-amino-3-hydroxybutanoic acid, e.g. (2S,3S)-2-amino-3-hydroxybutanoic acid; W1Me 2-amino-3-(1-methyl-1H-indol-3-yl)propanoic acid, e.g. (2S)-2-amino-3-(1-methyl-1H-indol-3-yl)propanoic acid (CAS number 1334509-86-2) [ka] tma 2-amino-4,4-dimethylpentanoic acid, e.g. (R)-2-amino-4,4-dimethylpentanoic acid [ka] Cbg 2-amino-2-cyclobutylacetic acid, e.g. (S)-2-amino-2-cyclobutylacetic acid (CAS number 1391630-31-1) [ka] Chg 2-amino-2-cyclohexylacetic acid, e.g. (2S)-2-amino-2-cyclohexylacetic acid (CAS number 161321-36-4) [ka] Cba 2-amino-3-cyclobutylpropanoic acid, e.g. (2S)-2-amino-3-cyclobutylpropanoic acid (CAS number 478183-62-9) [ka] 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 [ka] Hgn 2-amino-5-carbamoylpentanoic acid, e.g. (2S)-2-amino-5-carbamoylpentanoic acid (CAS number 1263046-43-0) [ka] Hph homophenylalanine; Nmm 2-amino-3-(methylcarbamoyl)propanoic acid, e.g. (2S)-2-amino-3-(methylcarbamoyl)propanoic acid (CAS number 149204-93-3) [ka] Ndm 2-amino-3-(dimethylcarbamoyl)propanoic acid, e.g. (2S)-2-amino-3-(dimethylcarbamoyl)propanoic acid (CAS number 138585-02-1) [ka] Hcit or hCit 2-amino-6-(carbamoylamino)hexanoic acid, e.g. (2S)-2-amino-6-(carbamoylamino)hexanoic acid (CAS number 201485-17-8) [ka] Q Glucamine 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 [ka] mBph 3-phenylphenylalanine; MeE 2-(methylamino)pentanedioic acid, such as (2S)-2-(methylamino)pentanedioic acid; MeN 3-carbamoyl-2-(methylamino)propanoic acid, such as (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 number 1813528-10-7) [ka] W1Me7Cl 2-amino-3-(7-chloro-1-methyl-1H-indol-3-yl)propanoic acid, for example (2S)-2-amino-3-(7-chloro-1-methyl-1H-indol-3-yl)propanoic acid [ka] W6C 6-chlorotryptophan; 3Py6NH2 2-amino-3-(6-aminopyridin-3-yl)propanoic acid, for example (2S)-2-amino-3-(6-aminopyridin-3-yl)propanoic acid [ka] Cit 2-amino-5-(carbamoylamino)pentanoic acid, e.g. (2S)-2-amino-5-(carbamoylamino)pentanoic acid [ka] F23dMe 2-amino-3-(2,3-dimethylphenyl)propanoic acid, e.g. (2S)-2-amino-3-(2,3-dimethylphenyl)propanoic acid (CAS number 1270295-08-3) [ka] F3C 3-chlorophenylalanine; Har 2-amino-6-carbamimidamidohexanoic acid, such as (2S)-2-amino-6-carbamimidamidohexanoic acid (CAS number 776277-76-0); bA 3-aminopropanoic acid; Kac or KAc (2S)-2-amino-6-acetamidohexanoic acid (CAS number 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-aminohexanedioic acid.

[0314]

Table 1

[0315]

Table 2

[0316]

Table 3

[0317]

Table 4

[0318]

Table 5

[0319]

Table 6

[0320]

Table 7

[0321]

Table 8

[0322] The molecular weight of the described peptides can vary. In some embodiments, the peptides have a molecular weight of about 0.1 to about 25 kDa. In some embodiments, the peptides have 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 peptides have 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.

[0323] The peptides described herein can be cyclized (i.e., macrocyclized). Cyclization can be achieved, although not ideally, through a single disulfide bond, or, more ideally, through a bond such as, but not limited to, a peptide bond, an alkyl bond, an alkenyl bond, an ester bond, a thioester bond, an ether bond, a thioether bond, a phosphate ether bond, an azo bond, a CSC bond, a CNC bond, a C=NC bond, a C=NO bond, an amide bond, a lactam bridge, a carbamoyl bond, a urea bond, a thiourea bond, an amine bond, a thioamide bond, or the like. In some embodiments, the peptide is a cyclic peptide cyclized through a peptide bond, an alkyl bond, an alkenyl bond, an ester bond, a thioester bond, an ether bond, a thioether bond, a phosphate ether bond, azo bond, a CNC bond, a C=NC bond, a C=NO bond, an amide bond, a lactam bridge, a carbamoyl bond, a urea bond, a thiourea bond, an amine bond, or a thioamide bond. In some embodiments, the cyclic peptide is cyclized through a thioether bond. In some embodiments, cyclic peptides are cyclized via oxime cyclization. Peptide cyclization may stabilize the peptide structure, thereby enhancing affinity for a target. Cyclization can occur between the N-terminus and C-terminus, or 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, peptides are cyclized via oxime cyclization. In some embodiments, peptides are cyclized between cysteine ​​and a haloacyl. In some embodiments, peptides include a haloacetyl group (e.g., chloroacetyl or bromoacetyl) at the N-terminus. In some embodiments, peptides include a haloacetyl group (e.g., chloroacetyl or bromoacetyl) at the C-terminus. In some embodiments, peptides include a Cys at the C-terminus. In some embodiments, peptides include a Cys at the C-terminus. In some embodiments, cyclization occurs via a thioether bond between Cys and the haloacetyl group. In some embodiments, cyclization occurs between the N-terminus and C-terminus of the peptide.

[0324] For example, the following amino acids having functional group A and corresponding functional group B can be used as amino acids for macrocyclization (see Table 4A). Either functional group A or functional group B can be located at the N-terminus. The amino acid having functional group A and the amino acid having functional group B can be the N-terminal amino acid, the C-terminal amino acid, or a non-terminal amino acid, respectively. 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.

[0325] In some embodiments, the amino acid (IA) can be, for example, a chloroacetylated amino acid. Examples of the chloroacetylated amino acid include N-chloroacetyl-L-alanine, N-chloroacetyl-L-phenylalanine, N-chloroacetyl-L-tyrosine, N-chloroacetyl-L-tryptophan, N-3-(2-chloroacetamido)benzoyl-L-phenylalanine, N-3-(2-chloroacetamido)benzoyl-L-tyrosine, N-3-(2-chloroacetamido)benzoyl-L-tryptophan, β-N-chloroacetyl-L-diaminopropanoic acid, γ-N-chloroacetyl-L-diaminopropanoic acid, β-N-chloroacetyl-L-diaminopropanoic acid, γ-N-chloroacetyl-L-alanine, β-N-chloroacetyl-L-phenylalanine, β-N-chloroacetyl-L-tyrosine, β-N-chloroacetyl-L-tryptophan, β-N-chloroacetyl-L-diaminopropanoic acid, γ ... N-chloroacetyl-L-diaminobutyric acid, σ-N-chloroacetyl-L-ornithine, ε-N-chloroacetyl-L-lysine, N-3-chloromethylbenzoyl-L-tyrosine, and 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).

[0326] [Table 9]

[0327] Examples of amino acids (IB) include, but are not limited to, cysteine, homocysteine, mercaptonorvaline, mercaptonorleucine, 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 the corresponding D-amino acid derivatives.

[0328] The cyclization method can be carried out according to the method described, for example, in Kawakami, T. et al., Nature Chemical Biology 5, 888-890 (2009); Yamagishi, Y. et al., ChemBioChem 10, 1469-1472 (2009); Sako, Y. et al., Journal of American Chemical Society 130, 7932-7934 (2008); or WO 2008 / 117833.

[0329] In some embodiments, for example, the amino acid (II-A) may be selected from propargylglycine, homopropargylglycine, 2-amino-6-heptynoic acid, 2-amino-7-octynoic acid, and 2-amino-8-nonynoic acid. Additionally, 4-pentynoylated or 5-hexynoylated amino acids may also be used. Examples of 4-pentenoylated 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-pentenoylamido)benzoyl-L-phenylalanine, N-3-(4-pentenoylamido)benzoyl-L-tyrosine, N-3-(4-pentenoylamido)benzoyl-L-tryptophan, β-N-(4-pentenoyl)-L-diaminopropanoic acid, γ-N-(4-pentenoyl)-L-diaminobutyric acid, σ-N-(4-pentenoyl)-L-ornithine, and ε-N-(4-pentenoyl)-L-lysine, and the corresponding D-amino acid derivatives thereof.

[0330] In some embodiments, for example, amino acid (II-B) may be selected from azidoalanine, 2-amino-4-azidobutanoic acid, azidooptonorvaline, azidonorleucine, 2-amino-7-azidoheptanoic acid, and 2-amino-8-azidooctanoic acid. Additionally, azidoacetylated or 3-azidopentanoylated amino acids may also be used. Examples of azidoacetylated amino acids include N-azidoacetyl-L-alanine, N-azidoacetyl-L-phenylalanine, N-azidoacetyl-L-tyrosine, N-azidoacetyl-L-tryptophan, N-3-(4-pentynoylamido)benzoyl-L-phenylalanine, N-3-(4-pentynoylamido)benzoyl-L-tyrosine, N-3-(4-pentynoylamido)benzoyl-L-tryptophan, β-N-azidoacetyl-L-diaminopropanoic acid, γ-N-azidoacetyl-L-diaminobutyric acid, α-N-azidoacetyl-L-ornithine, and ε-N-azidoacetyl-L-lysine, and the corresponding D-amino acid derivatives thereof.

[0331] The cyclization process can be carried out according to the method described in Sako, Y. et al., Journal of American Chemical Society 130, 7932-7934 (2008) or WO 2008 / 117833.

[0332] Examples of amino acid (II-A) include, but are not limited to, N-(4-aminomethyl-benzoyl)-phenylalanine (AMBF) and 4-3-aminomethyltyrosine.

[0333] Examples of the amino acid (III-B) include, but are not limited to, 5-hydroxytryptophan (WoH). The cyclization method can be carried out according to the method described in, for example, Yamagishi, Y. et al., ChemBioChem 10, 1469-1472 (2009) or WO 2008 / 117833.

[0334] Examples of amino acids (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.

[0335] Examples of amino acid (IV-B) include, but are not limited to, cysteine, homocysteine, mercaptonorvaline, mercaptonorleucine, 2-amino-7-mercaptoheptanoic acid, and 2-amino-8-mercaptooctanoic acid, amino acids obtained by protecting the SH group of these amino acids and then removing the protecting group, and the corresponding D-amino acid derivatives. The cyclization method can be carried out, for example, according to the method described in WO 2012 / 074129.

[0336] Examples of amino acids (VA) include, but are not limited to, N-3-chloromethylbenzoyl-L-phenylalanine, N-3-chloromethylbenzoyl-L-tyrosine, and N-3-chloromethylbenzoyl-L-tryptophan.

[0337] Examples of amino acids (VB) include, but are not limited to, cysteine, homocysteine, mercaptonorvaline, mercaptonorleucine, 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 the corresponding D-amino acid derivatives.

[0338] Amino acids IA-VA and IB-VB can be introduced into the peptide by known methods, either by chemical synthesis or translation and synthesis as described herein. In some embodiments, the cyclization reaction involves forming a thioether bond with an amino acid containing a sulfanyl group, such as cysteine, homocysteine, mercaptonorvaline, mercaptovaline, mercaptonorleucine, 2-amino-7-mercaptoheptanoic acid, and 2-amino-8-mercaptooctanoic acid.

[0339] 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 additional amine groups.Positively charged amino acids may contain heteroaryl substitutions such as pyridine, imidazole, pyrazole, or triazole, which have one or more ring nitrogen atoms.Negatively charged amino acids include, for example, amino acids containing additional carboxylic acid groups, such as glutamic acid.

[0340] In some embodiments, a cyclic peptide of 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, a cyclic peptide has a net charge of -3. In some embodiments, a cyclic peptide has a net charge of -2. In some embodiments, a cyclic peptide has a net charge of -1. In some embodiments, a cyclic peptide has a net charge of 0. In some embodiments, a cyclic peptide has a net charge of +1. In some embodiments, a cyclic peptide of Formula (I), Formula (I-1), Formula (I-2), Formula (Ia), Formula (Ib), or Formula (Ic) has a net charge of -4 or less. In some embodiments, a cyclic peptide has a net charge of -4. In some embodiments, a cyclic peptide of 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 aggregating the charges of each of the X1 through X12 amino acids (or each of the amino acids 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.

[0341] In some embodiments, the (cyclic) peptide of 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 aggregating the charges of each of the amino acids of the (cyclic) peptide.

[0342] In some embodiments, the (cyclic) peptides described herein (e.g., (cyclic) peptides of Formula (I), Formula (I-1), Formula (I-2), Formula (Ia), Formula (Ib), or Formula (Ic)) are configured to bind to EphA2 with a predetermined affinity, e.g., measured as plasma protein albumin binding (PPB) percentage. The % binding can be determined by HSA-HPLC method (measurement of drug protein binding by immobilized human serum albumin-HPLC). PPB can be determined in vitro by HPLC (e.g., Example B3) or other suitable means 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 according to the conditions described in Example B3. In some embodiments, 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 as determined by HPLC. 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.

[0343] In some embodiments, a conjugate described herein (e.g., a conjugate comprising a (cyclic) peptide of Formula (I), Formula (I-1), Formula (I-2), Formula (Ia), Formula (Ib), or Formula (Ic)) is configured to bind to a plasma protein with a predetermined affinity, e.g., measured as a plasma protein albumin binding (PPB) percentage. PPB can be determined in vitro by HPLC (e.g., Example B3) or other suitable means known in the art. In some embodiments, 1% to 99% of the conjugate binds to human serum albumin (HSA) in vitro, as determined by HPLC according to the conditions described in Example B3. In some embodiments, 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 as determined by HPLC. 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 conjugates bind to HSA in vitro. In some embodiments, about 40% to about 60% of the conjugates bind to HSA in vitro. In some embodiments, about 60% to about 99% of the conjugates bind to HSA in vitro. In some embodiments, about 60% to about 95% of the conjugates bind to HSA in vitro. In some embodiments, about 60% to about 80% of the conjugates bind to HSA in vitro. In some embodiments, about 60% to about 70% of the conjugates bind to HSA in vitro. In some embodiments, about 40% to about 50% of the conjugates bind 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.

[0344] In some embodiments, the (cyclic) peptide of formula (I), formula (I-1), formula (I-2), formula (Ia), formula (Ib), or formula (Ic) does not contain an S—S bond.

[0345] In some embodiments, peptides of the present disclosure can be cyclized by forming groups as shown in Table 4B.

[0346] [Table 10]

[0347] 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.

[0348] In some embodiments, peptides of the present disclosure, such as peptides of Formulas (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.

[0349] [Table 11]

[0350] In some embodiments, a conjugate comprising any one of the peptides in Table 1 may 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.

[0351] The peptides described herein may be peptidomimetics. For example, the peptides may contain non-peptide bonds and may contain one or more non-natural amino acids. Unless otherwise specified, each of the amino acids in the peptides described herein (except the natural amino acid glycine) may independently be in its D or L form. Both D and L forms are encompassed by the present disclosure.

[0352] In the present disclosure, the term amino acid encompasses derivatives of amino acids. Derivatives include, for example, amino acids obtained by modifying natural amino acids that make up proteins produced by cellular DNA-encoded biological materials. Examples of such unnatural amino acids include hydroxyproline and hydroxylysine, which are amino acids with an introduced hydroxy group, and diaminopropionic acid, which is an amino acid with an introduced amino group.

[0353] The peptides described herein may include N-substituted amino acids. In some embodiments, the N-substituted amino acids are derivatives 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 at the N-terminus of the peptide. In some embodiments, the N-substituted amino acid is a non-terminal amino acid.

[0354] In some embodiments, the peptides described herein comprise one or more amino acids in Tables 5A-5F.

[0355] [Table 12]

[0356] [Table 13]

[0357] [Table 14]

[0358] [Table 15]

[0359] Exemplary alkyl groups for Table 5D include methyl, ethyl, and propyl groups.

[0360] [Table 16]

[0361] [Table 17]

[0362] An amino acid used in the disclosed peptides may be substituted with a similar amino acid. In some embodiments, an amino acid may be substituted with another amino acid having a similar hydrophobicity. In some embodiments, an amino acid may be substituted with another amino acid having a similar hydrophilicity. In some embodiments, an amino acid may be substituted with another amino acid having a similar size. In some embodiments, an amino acid may be substituted with another amino acid having a similar charge. In some embodiments, an amino acid may be substituted with another amino acid having a similar functional group. In some embodiments, an amino acid may be substituted with another amino acid having the same functional group.

[0363] In some embodiments, the amino acids described herein may be substituted with variants thereof. Examples of amino acid substitutions or variants include derivatives having an amine, amide, ester, or carboxyl group at their C-terminus and / or N-terminus. Further examples of amino acid / peptide variants include those obtained by modifications such as phosphorylation, alkylation (e.g., methylation), acetylation, adenylation, ADP-ribosylation, or glycosylation, and fusion proteins obtained by fusion with another peptide or protein. These variants can be prepared by those skilled in the art using known methods or methods based thereon. Amino acid variants further include amino acids having the same functional group but different side chain lengths (e.g., LysAc vs. OrnAc and cysteine ​​vs. homocysteine). Amino acid variants further include amino acids having different aromatic moieties compared to standard amino acids (e.g., indole in tryptophan vs. 7-azaindole in 7-AzaTrp; phenyl in phenylalanine vs. pyridine in 4Py). Amino acid variants also include amino acids with optional substituents, i.e., optionally substituted amino acids. In some embodiments, the optionally substituted amino acid is selected from the group consisting of halogen, hydroxyl, cyano, amino, amido, nitro, ureido, C1-C6 alkyl, C1-C6 alkoxy, C6-C 10and optionally substituted with one or more substituents independently selected from aryl, C3-C6 cycloalkyl, 6-10 membered heterocycloalkyl, and 6-10 membered heteroaryl. In some embodiments, the optionally substituted amino acid is optionally substituted with one or more substituents independently selected from halogen, -CN, -NH, -NH(alkyl), -N(alkyl), oxo, -OH, -COH, -COalkyl, -C(=O)NH, -C(=O)NH(alkyl), -C(=O)N(alkyl), -S(=O)NH, -S(=O)NH(alkyl), -S(=O)N(alkyl), alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some embodiments, a substituent may be any of the substituents described herein, for example: halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO), imino (=NH), oximo (=N-OH), hydrazino (=N-NH), 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(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 (wherein t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, and heterocycle, any of which may be alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=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 -OR c -C(O)N(Ra)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), -Rb -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 —Rb—S(O)tN(R a )2 (wherein t is 1 or 2); where each R a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, and heterocycle, wherein each R a is, when valence allows, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=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(Ra)2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR 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)tR 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 (wherein t is 1 or 2); where each R b is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain; c is a straight or branched alkylene, alkenylene or alkynylene chain.

[0364] In some embodiments, amino acid variants are selected from amino acids having one, two, or three substituents based on the amino acid, where the substituents are independently halogen, —CN, —NH, —NH(C1-C3 alkyl), —N(C1-C3 alkyl), oxo, —OH, —CO2H, —CO2-C1-C3 alkyl, —C(═O)NH, —C(═O)NH(C1-C3 alkyl), —C(═O)N(C1-C3 alkyl), —S(═O)NH, —S(═O)NH(C1-C3 alkyl), —S(═O)N(C1-C3 alkyl), C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C6-C 10 It is selected from aryl, C3-C6 cycloalkyl, 6- to 10-membered heterocycloalkyl, and 6- to 10-membered heteroaryl.

[0365] In some embodiments, the variant is selected from an amino acid having one or two substituents based on the amino acid, where the substituents are independently selected from halogen, -CN, -NH, -NH(C1-C3 alkyl), -N(C1-C3 alkyl), oxo, -OH, -COH, -CO2-C1-C3 alkyl, -C(=O)NH, -C(=O)NH(C1-C3 alkyl), -C(=O)N(C1-C3 alkyl), and C1-C6 alkyl. In some embodiments, the variant is selected from an amino acid having one or two substituents based on the amino acid, where the substituents are independently selected from halogen, -CN, -NH, -NH(C1-C3 alkyl), -N(C1-C3 alkyl), and C1-C6 alkyl. In some embodiments, the variant is selected from an amino acid having one or two substituents based on the amino acid, where the substituents are independently selected from C1-C6 alkyl.

[0366] In some embodiments, an amino acid variant is selected from amino acids that have 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.

[0367] In some embodiments, a hydrophilic amino acid has a charged side chain. In some embodiments, a hydrophilic amino acid has a positive charge. In some embodiments, a hydrophilic amino acid has a negative charge. In some embodiments, a hydrophilic amino acid is a zwitterion (e.g., KCOpipzaa). In some embodiments, a hydrophilic amino acid comprises an -OH, COOH, -NH-, or NH2 moiety. In some embodiments, a hydrophilic amino acid comprises an -OH, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)NH3. In some embodiments, a hydrophilic amino acid comprises a C1-C6 hydroxyalkyl, a C1-C6 aminoalkyl, a -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 Contains alkyl side chains.

[0368] In some embodiments, the hydrophobic amino acid is uncharged. In some embodiments, the hydrophobic amino acid contains at least two consecutive carbon atoms. In some embodiments, the hydrophobic amino acid is either straight-chained or branched, and contains at least three consecutive carbon atoms. In some embodiments, the hydrophobic amino acid is either straight-chained or branched, and contains at least four consecutive carbon atoms. In some embodiments, the hydrophobic amino acid is either straight-chained or branched, and contains at least five consecutive carbon atoms. In some embodiments, the hydrophobic amino acid contains an ethylene moiety in its side chain. In some embodiments, the hydrophobic amino acid contains a propylene moiety in its side chain. In some embodiments, the hydrophobic amino acid contains a butylene moiety in its side chain. In some embodiments, the hydrophobic amino acid contains a phenyl moiety. In some embodiments, the hydrophobic amino acid contains a heteroaryl moiety. In some embodiments, the hydrophobic amino acid is Trp, Tyr, Phe, or a derivative thereof.

[0369] In some embodiments, the amino acid variant is selected from amino acids with the same functional group as the amino acid, and the variant has a side chain of a different length compared to the amino acid. In some embodiments, the amino acid variant is selected from amino acids with the same charge as the amino acid. In some embodiments, the amino acid variant is selected from amino acids with the same polarity as the amino acid. In some embodiments, an amino acid containing an aromatic group can be a variant of another amino acid with an aromatic group. In some embodiments, an amino acid containing a phenyl can be a variant of another amino acid with a phenyl. In some embodiments, an amino acid containing a heteroaryl can be a variant of another amino acid with a heteroaryl. 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.

[0370] In some embodiments, the amino acid variant is selected from amino acids that have a similar polarity and / or charge to the amino acid. For example, in some embodiments, a polar, uncharged amino acid can be another polar, uncharged amino acid (e.g., Hgn, Q, S, T, Q glucamine).

[0371] In some embodiments, an amino acid variant has the same number of hydrogen donors as the amino acid. In some embodiments, an amino acid variant has the same number of hydrogen acceptors as the amino acid.

[0372] In some embodiments, the variants have a molecular weight that does not vary by more than 14, 28, 30, 45, or 60 g / mol compared to the amino acid. In some embodiments, the variants have a molecular weight that does not vary by more than 14 g / mol compared to the amino acid. In some embodiments, the variants have a molecular weight that does not vary by more than 50 g / mol compared to the amino acid. In some embodiments, the variants have a molecular weight that does not vary by more than 28 g / mol compared to the amino acid.

[0373] Amino acid variants further include amino acids in which a functional group is replaced with another functional group having similar properties, for example, cysteine ​​may be replaced with homocysteine. In some embodiments, an aryl functional group may be replaced with an aryl or heteroaryl group. In some embodiments, a heteroaryl functional group may be replaced with an aryl or heteroaryl group. In some embodiments, an amino functional group may be replaced with an NH(alkyl) group.

[0374] As used herein, the phrase "conservative amino acid substitution" refers to the substitution of a functionally equivalent or similar amino acid. Conservative amino acid substitutions in a peptide result in a static change in the amino acid sequence of the peptide. For example, one or more amino acids with similar polarity behave functionally equivalently to each other, resulting in a static change in the amino acid sequence of the peptide. In general, substitutions in a particular group can be considered conservative with respect to structure and function. However, as will be apparent to those skilled in the art, the role played by a defined amino acid residue can be determined by its participation in the three-dimensional structure of the molecule containing the amino acid. For example, a cysteine ​​residue in its oxidized (disulfide) form may be less polar than its reduced (thiol) form. The long aliphatic portion of the arginine side chain can constitute an important structural and functional feature. Furthermore, side chains containing aromatic rings (tryptophan, tyrosine, phenylalanine) can contribute to ion-aromatic or cation-π interactions. In such cases, substitution of amino acids with these side chains with amino acids belonging to acidic or nonpolar groups can be structurally and functionally conservative. Residues such as proline, glycine, and cysteine ​​(in disulfide form) have a direct effect on the three-dimensional structure of the main chain and often cannot be substituted without structural distortion.

[0375] Conservative amino acid substitutions include specific substitutions based on side chain similarity (e.g., substitutions described in Lehninger, Biochemistry, Revised 2nd Edition, published in 1975, pp. 73-75: L. Lehninger, Biochemistry, 2nd edition, pp. 73-75, Worth Publishers, New York (1975)), which are incorporated herein by reference, and typical substitutions, as shown below.

[0376] Hydrophobic amino acids include amino acids that exhibit hydrophobicity, including alanine (also called "Ala" or simply "A"), glycine (also called "Gly" or simply "G"), valine (also called "Val" or simply "V"), leucine (also called "Leu" or simply "L"), isoleucine (also called "Ile" or simply "I"), proline (also called "Pro" or simply "P"), phenylalanine (also called "Phe" or simply "F"), tryptophan (also called "Trp" or simply "W"), tyrosine (also called "Tyr" or simply "Y"), and methionine (also called "Met" or simply "M").

[0377] Exemplary hydrophobic amino acids can be further divided into the following groups: Aliphatic amino acids: Amino acids with fatty acids or hydrogens in their side chains, including Ala, Gly, Val, Ile, and Leu. Aliphatic / branched chain amino acids: Amino acids with branched chain fatty acids in their side chains, including Val, Ile, and Leu. Aromatic amino acids: Amino acids with an aromatic ring in the side chain, including Trp, Tyr, and Phe.

[0378] In some embodiments, the hydrophobic amino acid has four or more carbon atoms in its side chain (a straight, branched, or cyclic carbon side chain), e.g., Leu, Hcit, Cbg, Chg, or Cba, each of which is optionally N-methylated.

[0379] Hydrophilic amino acids include amino acids that exhibit hydrophilicity, including, for example, serine (also called "Ser" or simply "S"), threonine (also called "Thr" or simply "T"), cysteine ​​(also called "Cys" or simply "C"), asparagine (also called "Asn" or simply "N"), glutamine (also called "Gln" or simply "Q"), aspartic acid (also called "Asp" or simply "D"), glutamic acid (also called "Glu" or simply "E"), lysine (also called "Lys" or simply "K"), arginine (also called "Arg" or simply "R"), and histidine (also called "His" or simply "H").

[0380] Exemplary hydrophilic amino acids can be further divided into the following groups: Acidic amino acids: Amino acids with acidic side chains, including Asp and Glu. Basic amino acids: Amino acids whose side chains are basic, including Lys, Arg, and His. Neutral amino acids: Amino acids whose side chains are neutral, including Ser, Thr, Asn, Gln, and Cys.

[0381] 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 glucamine having a glucamine moiety added to the NH2-terminus of the side chain).

[0382] In some embodiments, the peptides described herein include amino acids that influence backbone orientation, such as Gly and Pro. In some embodiments, the peptides described herein include sulfur-containing amino acids, such as Cys and Met. In some embodiments, the peptides described herein include amino acids that include an aromatic ring, which may be optionally substituted. Examples of amino acids that include an aromatic ring include F (Phe; phenylalanine), Y (Tyr; tyrosine), and W (Trp; tryptophan).

[0383] In some embodiments, W or a variant thereof 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 replaced, or an amino acid having a substituent in the benzene ring of W, etc.

[0384] In some embodiments, F or a variant thereof is F (phenylalanine), an amino acid, wherein (i) the phenyl ring of F is not selected from the group consisting of —OH, —CN, —C 1~3 (ii) the 6-membered heteroaryl ring is substituted with one or two substituents independently selected from -OH, -CN, -C 1~3 or (iii-1) an amino acid having a heteroatom in the phenyl ring of F in the side chain; (iii-2) a derivative amino acid of F in which the 6-membered heteroaryl ring in the side chain is substituted, etc. In some embodiments, F or a variant thereof is optionally N-methylated.

[0385] In some embodiments, W, Y, or a variant thereof can be an amino acid having either W, Y, a 6-membered aryl or heteroaryl, or a 9- or 10-membered bicyclic aryl or heteroaryl bonded to the α-carbon through a carbon (e.g., a methylene group). In some embodiments, the 6-, 9-, and 10-membered heteroaryl have one heteroatom (e.g., N), and the 6-, 9-, and 10-membered aryl or heteroaryl are optionally substituted with one or two substituents independently selected from -methyl, -ethyl, -Cl, and -F. In certain embodiments, W or Y or a variant thereof is W1Me, W1Me7Cl, or F23dMe, Na11, Na12, W1Et, Na121N, 3Bzf, 3Bzt, Na15N, Na14N, Na124N, Na128N, F23dC, or W1Me7N. In some embodiments, the variant of W is W1Me. In some embodiments, the W variant is W1Me7Cl. In some embodiments, the Y variant is F23dMe.

[0386] In some embodiments, the amino acids described herein are N-alkylated.

[0387] In some embodiments, the amino acids described herein are not N-alkylated (e.g., amino acids having an -H on the α-amino group). In certain embodiments, such amino acids are A, E, N, K, Q Glucamine, KCOpipzaa,Q, Hse, Cit, Hcit, KAc, DapAc, OrnAc, T, a1T, Aib, or 3Py6NH2, more preferably V, Q Glucamine, Cit, Hcit, K, or 3Py6NH2.

[0388] Examples of amino acids include naturally occurring protein L-amino acids, unnatural amino acids, and chemically synthesized compounds having properties known in the art as characteristic of amino acids. 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 of which has a backbone structure different from that of natural amino acids; amino acids with side chain structures different from natural amino acids (such as norleucine and homohistidine); amino acids with an additional methylene in their side chains (such as "homo" amino acids, homophenylalanine and homohistidine); and amino acids obtained by replacing a carboxylic acid functional group in their side chains with a sulfonic acid group (such as cysteic acid).

[0389] 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 having -H on the α-amino group). In certain embodiments, such amino acids are A, E, N, K, Q Glucamine, KCOpipzaa, Q, Hse, Cit, Hcit, KAc, DapAc, OrnAc, T, a1T, Aib, or 3Py6NH2, more preferably V, Q Glucamine, Cit, Hcit, K, or 3Py6NH2.

[0390] The peptides described herein may contain one or more unnatural amino acids. Unnatural amino acids include, but are not limited to, (1) amino acids corresponding to amino acid residues on polypeptides that are modified after expression (e.g., phosphorylated tyrosine, acetylated lysine, or farnesylated cysteine), (2) naturally occurring amino acids that are unavailable for expression on the ribosome, and (3) artificial amino acids that do not occur in nature (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-methyl-phenylalanine, O-4-allyl-L-tyrosine, 4-propyl-L-tyrosine, tri-O-acetyl-GlcNAcp-serine, L-Dopa, fluorine, and the like. Examples of suitable tyrosine include boronated 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 azido-lysine (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, hydroxyl, alkenyl, alkyne, ether, thiol, sulfonyl, seleno, ester, thioacid, borate, boronate, phospho, phosphono, phosphine, heterocyclic, enone, imine, aldehyde, hydroxylamine, keto, 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 photoisomerizable amino acid; a thiotin- or biotin analog-containing amino acid; 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 with a long side chain; an amino acid containing a toxic group; a sugar-substituted amino acid; a carbon-linked sugar-containing amino acid; a redox-active amino acid; a hydroxy-containing acid; an aminothioacid; an α,α-substituted amino acid; an aβ-amino acid; a cyclic amino acid other than proline or histidine, or an aromatic amino acid other than phenylalanine, tyrosine, or tryptophan.

[0391] Non-natural amino acids include, for example, N-alkylamino acids in which the above-mentioned natural amino acids are N-alkylated, e.g., those in which the nitrogen that forms the peptide bond is modified with a branched or unbranched lower alkyl group (e.g., C1-C5, C1-C3, and C1). Exemplary N-alkylamino acids include, for example, N-ethylamino acids, N-butylamino acids, and N-methylamino acids. Also included are amino acids in which a functional group is further added to the side chain of a natural amino acid or substituted with another functional group (e.g., amino acids having substitutions or additions to moieties such as arylene groups, alkylene groups, etc. in the side chain; amino acids in which the arylene groups or alkyl groups in the side chain have increased C numbers; amino acids having substitutions in the aromatic rings in the side chain; heterocyclic or fused cyclic amino acids, etc.). Further exemplary N-alkylamino acids include, for example, N-alkyllysine and N-methyllysine. Further exemplary N-alkylamino acids include, for example, N-methyllysine bound to an albumin binder.

[0392] Non-limiting examples of unnatural amino acids include N-methyl amino acids, da, kCOpipzaa, dahp, df3CON, 4Py, W7N, QPh, aIT, W1Me, Cbg, Chg, Cba, Hgl, Hgn, Nmm, Ndm, Hcit, Qglucamine, Hph, W1Me7N, W1Me7Cl, 3Py6NH2, Cit, F23dMe, Har, bA, Kac, dkAc , MeF, Me3Py, MeHph, MeF3CN, MeF3H, MeE, MeN, MeF4C, Na1, Na12, W1Et, Na11N, 3Bzf, 3Bzt, a15N, Na11N, Na12N, Na12N, Na128N, F23dMe, F23dC, W1Me7N, W1Me7Cl, Hse, DapAc, OrnAc, Alb, etc. Note that D-amino acids such as da can be classified as D-amino acids, but they can also be classified according to the properties of their side chains, and N-methyl amino acids can be classified as N-alkyl amino acids, which can also be classified according to the properties of the side chain.

[0393] In some embodiments, the unnatural amino acids incorporated into the peptide include one or more of the following: 1) ketone functional groups (as found in para- or meta-acetyl-phenylalanine) that 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. 2003 Jan. 7;100(1):56-61; Bioorg Med Chem Lett. 2006 Oct. 15;16(20):5356-9. Genetic introduction of a diketone-containing amino acid into proteins. Zeng H, Xie J, Schultz PG), 2) azides (as found in p-azido-L-phenylalanine) that can react with alkynes via copper-catalyzed "click chemistry" or strain-promoted (3+2) cycloaddition to form the corresponding triazoles (Addition of p-azido-L-phenylalanine to the genetic code of Escherichia coli). coli.Chin JW,Santoro SW,Martin AB,King DS,Wang L,Schultz P GJ Am Chem Soc.2002 Aug.7;124(31):9026-7;Adding amino acids with novel reactivity to the genetic code of Saccharomyces cerevisiae.Deiters A,Cropp TA,Mukherji M,Chin JW,Anderson JC,Schultz P GJ Am Chem Soc.2003 Oct.1;125(39):11782-3) or can be reacted with aryl phosphines via Staudinger ligation to form the corresponding amides (Selective Staudinger modification of proteins containing p-azidophenylalanine. Tsao ML, Tian F, Schultz P G. Chembiochem. 2005 December;6(12):2147-9); 3) alkynes, which can be reacted 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. 2005 March;15(5):1521-4); and 4) boronic acids (boronates), which can be reacted specifically with compounds containing two or more appropriately spaced hydroxyl groups or can 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 ML, Lee JW, Groff D, Liu W, Schultz PG). .

[0394] The peptides of the present disclosure encompass various derivatives thereof. Examples of derivatives include derivatives having an amide group, an ester group, or a carboxyl group at the C-terminus and / or N-terminus. Further examples of peptide derivatives include those obtained by modifications such as phosphorylation, methylation, acetylation, adenylation, ADP-ribosylation, or glycosylation, and fusion proteins obtained by fusion with another peptide or protein. These derivatives can be prepared by those skilled in the art using known methods or methods based thereon.

[0395] In some embodiments, the peptides described herein comprise a basic amino acid. Examples of basic amino acids include arginine, lysine, citrulline, ornithine, creatine, histidine, diaminobutanoic acid, and diaminopropionic acid.

[0396] In some embodiments, provided herein are peptides having 90% or greater sequence identity to any of the sequences disclosed herein, in some embodiments, the sequence identity is at least 95% or 99%.

[0397] 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 BT5528, BT1718, and BT8009. Exemplary bicyclic peptides are described in U.S. Patent Application Publication No. 20180200378, U.S. Patent No. 10,441,663, U.S. Patent No. 8,680,022B2, U.S. Patent Application Publication No. 20180280525, and U.S. Patent Application Publication No. 20200215199, each of which is incorporated herein by reference in its entirety. In some cases, cyclizing a peptide can improve protease resistance, improve metabolic stability, and limit conformational changes, resulting in increased rigidity, membrane permeability, and affinity for target proteins.

[0398] In some embodiments, the peptides of the present disclosure have a cyclic structure to which a chloroacetylated amino acid and a cysteine ​​residue present in the peptide are bonded. In one aspect, the peptide has a cyclic structure to which an N-terminal amino acid and a cysteine ​​residue present in the peptide are bonded. In some embodiments, the peptide has a cyclic structure to which an N-terminal amino acid and a 13th cysteine ​​residue present in the peptide are bonded. In some embodiments, the peptide has a cyclic structure to which a chloroacetylated N-terminal amino acid and a 12th cysteine ​​residue present in the peptide are bonded. "Chloroacetylation" can be replaced with "haloacetylation" using another halogen. Furthermore, "acetylation" can be "acylation" using an acyl group other than an acetyl group.

[0399] In some embodiments, the peptide is a lariat peptide. Lasso peptides can be synthesized or naturally produced by bacteria, and they have a unique, twisted, lariat-like fold that provides a 3D arrangement of functional groups for engaging with biological targets. This lariat structure can enable beneficial properties such as affinity, stability, and potent biological activity. Suitable lariat structures can be designed algorithmically. Exemplary lasso peptides are Hegemann, JD, et al., Lasso Peptides: An Intriguing Class of Bacterial Natural Products, Acc. Chem. Res., 2015, 48, 1909-1919; Tietz, JI, et al., A new genome-mining tool redefines the lasso peptide biosynthetic landscape, Nature Chem Bio,2017,13,470-478;DiCaprio,AJ,et al.,Enzymatic Reconstitution and Biosynthetic Investigation of the Lasso Peptide Fusilassin,J.Am.Chem.Soc.,2019,141,290-297;Al Toma,RS,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.

[0400] Further exemplary peptides include BMS-753493, somatostatin, octreotide, octreotate, lanreotide, pasireotide, JR-11, L-779,976, BIM-23120, satreotide, depreotide, 18F-KYNDRLPLYISNP (SEQ ID NO: 274), CaIX-P1, and FAP-2286.

[0401] The peptides of the present disclosure include salts thereof. Salts of the peptides used may be salts with physiologically acceptable bases or acids. 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-bromophenylsulfonic 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.

[0402] Furthermore, a linker can be further added to the (cyclic) peptide. Examples of linkers include the aforementioned amino acid linkers (peptide linkers), chemical linkers, fatty acid linkers, nucleic acid linkers, and sugar chain linkers, or conjugates such as chemical linkers and peptide linkers. An example of a chemical linker is a PEG (polyethylene glycol) linker. For example, a PEG linker can contain 1 to 24 ethylene glycol units. Furthermore, the linker can be a fatty acid linker containing a divalent chemical moiety derived from a fatty acid. The linker contains at least one amino acid, and can be, for example, a glycine-rich peptide such as a peptide having the sequence [Gly-Gly-Gly-Gly-Ser]n (where n is 1, 2, 3, 4, 5, or 6 (SEQ ID NO: 275)), for example, one described in U.S. Pat. No. 7,271,149, incorporated herein by reference, or a serine-rich peptide linker described in U.S. Pat. No. 5,525,491, incorporated herein by reference. In a non-limiting example, the physical properties (e.g., solubility) of a peptide may be altered by the addition of a linker. In one embodiment, the amino acid linker comprises an amino acid sequence set forth in any one of SEQ ID NOs: 1 to 171.

[0403] The linker can be added at any position. For example, it can be attached to a Cys located at the C-terminus or to an amino acid contained in the cyclic peptide. In some cases, it is attached to a Cys or a variant thereof located at the C-terminus. In this case, the linker is attached to the -COOH of the Cys residue. It may be possible to add one to several amino acids to the C-terminus of such a Cys residue, and then a linker can be added to that end. For example, Gly is added to the C-terminus of Cys in a cyclic peptide, and then the -COOH of Gly is bound to a linker such as a PEG linker or an amino acid linker. In another example, the linker is attached to the side chain of an amino acid, preferably Lys, in the cyclic peptide. In this case, for example, the linker is attached to the side chain of Lys at X5, X8, or X10.

[0404] EphA2-binding peptides and peptides with EphA2 antagonist activity EPH receptor A2 (ephrin type-A receptor 2) is a protein encoded by the EPHA2 gene in humans. EphA2 can be upregulated in multiple cancers and is often correlated with disease progression, metastasis, and poor prognosis, for example, in solid tumors such as breast, lung, stomach, pancreas, prostate, liver, and glioblastoma.

[0405] Eph receptor tyrosine kinases (Ephs) belong to a large group of receptor tyrosine kinases (RTKs), which are kinases that phosphorylate proteins on tyrosine residues. Ephs and their membrane-bound ephrin ligands (ephrins) can regulate cell location and tissue organization. Functional and biochemical Eph responses can occur at higher ligand oligomerization states.

[0406] Among other patterning functions, various Ephs and ephrins have been shown to play roles in vascular development. Knockout of EphB4 and ephrin-B2 can result in the inability to remodel capillary beds into blood vessels and embryonic lethality. Persistent expression of several Eph receptors and ephrins has also been observed in newly formed adult microvessels (Brantley-Sieders et al. (2004) Curr Pharm Des 10, 3431-42). The unregulated reappearance of some ephrins and their receptors in adults may contribute to tumor invasion, metastasis, and angiogenesis. Furthermore, some Eph family members can be overexpressed on tumor cells derived from various human tumors (Booth et al. (2002) Nat Med 8, 1360-1).

[0407] 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 examples, the peptides bind to human EphA2 (hEphA2) and have hEphA2 antagonist activity.

[0408] As used herein, the term "EphA2" refers to any form of EphA2 and variants thereof that retain at least some of the activity of EphA2. EphA2 includes all native sequences of EphA2 in mammals, such as humans, dogs, cats, horses, and cows, unless specifically referred to as human EphA2 (hEphA2). 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). [ka]

[0409] Another isoform of human EphA2 is shown below as SEQ ID NO: 277 (isoform 2, P29317-2): [ka] It may have the sequence set forth in

[0410] As used herein, the phrases "having binding activity for EphA2" or "binding to EphA2" refer to having binding activity to EphA2. The binding site of the peptides of the present invention on EphA2 is not limited, and the peptides can bind to any location on the EphA2 protein. Binding to EphA2 can be measured by any known method for measuring intermolecular binding. Non-limiting examples include, for example, surface plasmon resonance (SPR) assay, scattering analysis and / or competitive binding assays such as radioimmunoassay (RIA), enzyme immunoassay (EIA), and sandwich and competitive assays, and any suitable known method, including different variations of the examples shown, known in the art.

[0411] In some embodiments, peptides of the invention compete for binding to 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, peptides compete for binding to human EphA2 at one or more amino acid residues selected from Asp53, Phe156, and Glu157. In some embodiments, peptides compete for binding to human EphA2 at Asp53, Glu157, or both.

[0412] In one aspect, the binding affinity of the peptide of the present technology is 100nM or less, as determined by Kd in surface plasmon resonance (SPR) analysis.In some embodiments, the Kd of the peptide of the present technology is 100nM or less, 50nM or less, 30nM or less, 20nM or less, 10nM or less, 5nM or less, 4nM or less, 3nM or less, 2nM or less, 1nM or less, 0.9nM or less, 0.5nM or less, 0.4nM or less, 0.3nM or less, 0.2nM or less, 0.1nM or less, 0.09nM or less, 0.08nM or less, 0.07nM or less, 0.06nM or less, 0.05nM or less, 0.04nM or less, 0.03nM or less, 0.02nM or less, or 0.01nM or less.

[0413] In some embodiments, the peptides described herein have a binding affinity for human EphA2 of 1, 5, 10, 50, 100, 200, 500, 1000, 5000, or 10,000 nM or less, as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, the peptides described herein have a binding affinity for human EphA2 of 100 nM or less, as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, the peptides described herein have a binding affinity for human EphA2 of 1 nM or less, as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, the peptides described herein have a binding affinity for human EphA2 of 2 nM or less, as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, the peptides described herein have a binding affinity for human EphA2 of 5 nM or less, as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, the peptides described herein have a binding affinity for human EphA2 of 10 nM or less as determined by Kd in surface plasmon resonance (SPR) analysis.

[0414] In some embodiments, the conjugates described herein have a binding affinity for human EphA2 of 1, 5, 10, 50, 100, 200, 500, 1000, 5000, or 10,000 nM or less, as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, the conjugates described herein have a binding affinity for human EphA2 of 100 nM or less, as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, the conjugates described herein have a binding affinity for human EphA2 of 1 nM or less, as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, the conjugates described herein have a binding affinity for human EphA2 of 2 nM or less, as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, the conjugates described herein have a binding affinity for human EphA2 of 5 nM or less as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, the conjugates described herein have a binding affinity for human EphA2 of 10 nM or less as determined by Kd in surface plasmon resonance (SPR) analysis.

[0415] In one aspect, the binding affinity of a peptide or conjugate of the present disclosure is 100 nM or less as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, the Kd of a peptide or conjugate of the present disclosure is 100 nM or less, 50 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.9 nM or less, 0.5 nM or less, 0.4 nM or less, 0.3 nM or less, 0.2 nM or less, 0.1 nM or less, 0.09 nM or less, 0.08 nM or less, 0.07 nM or less, 0.06 nM or less, 0.05 nM or less, 0.04 nM or less, 0.03 nM or less, 0.02 nM or less, or 0.01 nM or less.

[0416] Unnatural amino acids In certain embodiments, the peptides and conjugates described herein comprise one or more unnatural amino acids that are not one 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 shown in the table below.

[0417] [ka] [ka] [ka] [ka]

[0418] Linkers and Peptide Linkers The peptides described herein can be linked to one or more linkers before such peptide linker intermediates are further linked to payload molecules to form the conjugates described herein. Thus, the conjugates described herein can include one or more linkers. In some embodiments, the linker covalently bonds the peptide to the payload molecule in the conjugate. In some other embodiments, the peptide is directly linked to the payload molecule without a linker. In some embodiments, the present disclosure describes a linker that functions as a spacer.

[0419] The linker may include several intervening atoms (in the linear chain, excluding pendant 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 to 100 intervening atoms between the payload molecule and the binding peptide. In some embodiments, the linker includes 2 to 60 intervening 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 intervening atoms between the payload molecule and the binding peptide. In some embodiments, the linker includes 3 to 30 intervening atoms between the payload molecule and the binding peptide. In some embodiments, the linker includes 5 to 25 intervening atoms between the payload molecule and the binding peptide. In some embodiments, the linker includes 6 to 18 intervening atoms between the payload molecule and the binding peptide. In some embodiments, the linker includes 10 to 20 intervening atoms between the payload molecule and the binding peptide. Intervening atoms can include one or more carbons and, optionally, one or more heteroatoms such as O and N. In some embodiments, intervening atoms can 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, intervening atoms include 0, 1, 2, 3, 4, 5, or 6 nitrogens. In some embodiments, intervening atoms include 0, 1, 2, 3, 4, 5, 6, 7, or 8 oxygens. In some embodiments, intervening atoms include 1 to 6 nitrogens and 0 to 4 oxygens.

[0420] 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 a K, KK, or KKK sequence. 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 in the linker are unnatural 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.

[0421] The linkers described herein can be attached to the N-terminus of the peptide, the C-terminus of the peptide, or a non-terminal amino acid of the peptide, or can be attached to the peptide via a combination of the above. In some embodiments, the linker is attached to the peptide via its N-terminus. In some embodiments, the linker is attached to the peptide via a C-terminal cysteine ​​residue. In some embodiments, the linker is attached to the peptide via an N-terminal cysteine ​​residue. In some embodiments, the linker is attached to the peptide via its C-terminus. In some embodiments, the linker is attached to the peptide via a non-terminal amino acid. The linker can be attached to the peptide, the payload molecule, or both, for example, via a chemically reactive group. Exemplary chemically reactive groups include, but are not limited to, a free amino, imino, hydroxyl, thiol, or carboxyl group (e.g., at the N-terminus or C-terminus, the epsilon-amino group of one or more lysine residues, the free carboxylic acid groups of one or more glutamic acid or aspartic acid residues, or the sulfhydryl group of one or more cysteine ​​residues). The site at which the linker is attached to the peptide can be a natural or unnatural amino acid of the peptide, and / or it can be introduced into the peptide by, for example, recombinant DNA techniques (e.g., by introducing a cysteine ​​or protease cleavage site into the amino acid sequence) or protein biochemistry (e.g., reduction, pH adjustment, or proteolysis). Exemplary methods for attaching linkers include carbodiimide reactions, reactions using bifunctional substances such as dialdehydes or imidoesters, Schiff base reactions, Suzuki-Miyaura cross-coupling reactions, isothiocyanates as coupling agents, and click chemistry.

[0422] The linker can have a predetermined length, thereby linking the payload molecule and the peptide while allowing an appropriate distance between them. 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.

[0423] A linker can comprise flexible and / or rigid regions. Exemplary flexible linker regions include those comprising Gly and Ser residues ("GS" linkers), glycine residues, alkylene chains, PEG chains, etc. Exemplary rigid linker regions include those comprising alpha-helix-forming sequences (e.g., EAAAK (SEQ ID NO: 278)), proline-rich sequences, and double- and / or triple-bond-rich regions.

[0424] 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 cleaved by an intracellular peptidase or protease enzyme, including, but not limited to, a lysosomal or endosomal protease. In some embodiments, the peptide linker is at least two amino acids long or at least three amino acids long. Cleaving agents may include cathepsins 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 hydrolyzable under acidic conditions. For example, the linker may be an acid-labile linker (e.g., hydrazone, semicarbazone, thiosemicarbazone, cis-aconitic acid amide, orthoester, acetal, ketal, etc.) that is hydrolyzable in the lysosome. Such linkers may be relatively stable under neutral pH conditions, such as those in blood, but are unstable below pH 5.5 or 5.0, which is approximately the pH of the lysosome. In some embodiments, the hydrolyzable linker is a thioether linker.

[0425] In some embodiments, the linker comprises an amino acid sequence, such as a combination of amino acid sequences and flexible and / or rigid regions, as exemplified in Table 6B under the "Linker" column. For example, PDC_EphA2-00010011-C003 comprises a linker comprising amino acid residues bA-dk. In another example, PDC_EphA2-00001417-C004 comprises a linker comprising a combination of amino acid residues and PEG,kA-dk-(PEG8c-PEG2c).

[0426] In some embodiments, the linker can comprise an amino acid sequence, or a combination of an amino acid sequence and a flexible and / or rigid region, such as those provided in Table 13 (see the "Linker / Payload" column). For example, in Table 13, biotin, SulfoCys5, is shown as the payload. PDC_EphA2-00010011-C003 comprises a linker comprising the amino acid residues bA-dk.

[0427] In some embodiments, the linker comprises one or more of 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 one or more of substituted or unsubstituted C1-C 30 In some embodiments, the linker comprises an alkylene. 1~10 In some embodiments, the linker comprises a structure selected from the following: [ka] and structures derived from any one of them.

[0428] In some embodiments, the linker comprises a click chemistry residue. In some embodiments, the linker is attached to the peptide, the payload molecule, or both via click chemistry, thereby forming the click chemistry residue. For example, the peptide may comprise an azide group (at the N-terminus or C-terminus or a non-terminal amino acid) that reacts with the alkyne moiety of the linker. In another example, the peptide may comprise an alkyne group (at the N-terminus or C-terminus or a non-terminal amino acid) that reacts with the azide of the linker. The payload molecule and the linker may be attached in a similar manner. 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 [ka] (DBCO-azide residue), [ka] 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 a residue of a nitrone dipolar cycloaddition. In some embodiments, the linker comprises a residue of a tetrazine ligation. In some embodiments, the linker comprises a residue of a quadricyclane ligation. Exemplary groups of click chemistry residues are shown in Hein at al., "Click Chemistry, A Powerful Tool for Pharmaceutical Sciences," Pharmaceutical Research volume 25, pages 2216-2230 (2008); Thirumurugan et al., "Click Chemistry for Drug Development and Diverse Chemical-Biology Applications," Chem. Rev. 2013, 113, 7, 4905-4979; U.S. Patent Application Publication No. 20160107999A1; U.S. Patent No. 10266502B2; and U.S. Patent Application Publication No. 20190204330A1, each of which is incorporated by reference in its entirety.

[0429] In some embodiments, the linkers described herein contain two or more motifs. In some embodiments, one or more of the motifs are attached via click chemistry so that they click in / out of the linker. Each motif within the linker can have an independent function. For example, the linker can contain a motif that functions to adjust plasma half-life and / or a motif that functions as a spacer between the peptide and the payload molecule.

[0430] In some embodiments, the linker has the structure: [ka] 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 + -, -N(R L )2 + -(C1~C 30 alkylene)-, or a click chemistry residue; Each R L are 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; n is 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).

[0431] In some embodiments, the linker has the structure: [ka] wherein 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)-.

[0432] In some embodiments, the linker of formula (II-1) has the structure of formula (II-1a): [ka] During the ceremony, L 1 and L3 each independently represents -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)-; L 2 is absent or substituted or unsubstituted C1-C 30 Alkylene, or substituted or unsubstituted C1-C 30 It is heteroalkylene.

[0433] In some embodiments, the linker comprises a structure of formula (II-1b): [ka] During the ceremony, L 1 and L 5 each independently represents -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 -, -NRL S(=O)2-, -S(=O)2NR L -, -C(=O)NR L S(=O)2-, -S(=O)2NRLC(=O)-, substituted or unsubstituted 5-6 membered cycloalkyl, or substituted or unsubstituted 5-6 membered heterocycloalkyl; L 2 , L 3 and L 4 are each independently absent, 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 substituted or unsubstituted C1-C 30 It is heteroalkylene.

[0434] In some embodiments, L 1 is -NH-.

[0435] In some embodiments, L 2 is absent. In some embodiments, L 2 is a substituted or unsubstituted C1 to C 30 Alkylene, or substituted or unsubstituted C1-C 30 In some embodiments, L is heteroalkylene. 2 is a substituted or unsubstituted C1 to C 30 In some embodiments, L is alkylene. 2 is a substituted or unsubstituted C1 to C 30 In some embodiments, L is heteroalkylene. 2 is a substituted or unsubstituted C1 to C 18 Alkylene, or substituted or unsubstituted C1-C 18 In some embodiments, L is heteroalkylene. 2 is optionally substituted. In some embodiments, L 2 is optionally 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)ORL , -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 is substituted with one or more substituents selected from 2 is a C1-C alkyl group optionally substituted with one or more substituents selected from -OH, -SH, oxo, amino, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, and C1-C6 aminoalkyl; 30 In some embodiments, L is heteroalkylene. 2 -OH, -SH, oxo, amino, C6 to 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(RL)2, and -NR L C(=O)OR L is optionally substituted with C1-C6 alkyl, which is optionally further substituted with one or more substituents selected from:

[0436] In some embodiments, L 3 is —NH—. In some embodiments, L 3 does not exist.

[0437] In some embodiments, L 4 is absent. 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 substituted or unsubstituted C1-C 30 It is heteroalkylene.

[0438] In some embodiments, L5 is —NH—. In some embodiments, L 5 does not exist.

[0439] 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 absent, 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 substituted or unsubstituted C1-C 30 heteroalkylene, where L 1 is attached to a payload molecule, and L 5 is conjugated to an EphA2-binding peptide.

[0440] In some embodiments of Formula (II-1b), L 2 is unsubstituted C1 to C 12 alkylene, and L 3 and L 4 does not exist.

[0441] In some embodiments, the linker is 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.

[0442] In some embodiments, L 1 each independently represents -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, or substituted or unsubstituted C1-C 30 heteroalkylene, and in some embodiments, L 1 -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 LS(=O)2- or -S(=O)2NR L In some embodiments, L 1 is —O—, —NH—, —S(═O)—, —S(═O)—, or —C(═O)—. In some embodiments, L 1 is —C(═O)NH— or —NHC(═O)—. In some embodiments, L 1 is C3~C 15 Cycloalkyl, or substituted or unsubstituted C1-C 12 In some embodiments, L is heterocycloalkyl. 1 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, L 1 is a substituted or unsubstituted C1-C 30 In some embodiments, L is alkylene. 1 is a substituted or unsubstituted C2 to C 30 In some embodiments, L is alkenylene. 1 is a substituted or unsubstituted C1-C 30 In some embodiments, L is heteroalkylene. 1 is a substituted or unsubstituted C5-C 25 In some embodiments, L is heteroalkylene. 1 is a substituted or unsubstituted C5-C 12 It is heteroalkylene.

[0443] In some embodiments, L 2 each independently represents -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)NRL -, -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, and in some embodiments, L 2 -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 In some embodiments, L 2 is —O—, —NH—, —S(═O)—, —S(═O)—, or —C(═O)—. In some embodiments, L 2 is —C(═O)NH— or —NHC(═O)—. In some embodiments, L 2 is a substituted or unsubstituted C3 to C 15Cycloalkyl, or substituted or unsubstituted C1-C 12 In some embodiments, L is heterocycloalkyl. 2 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, L 2 is a substituted or unsubstituted C1-C 30 In some embodiments, L is alkylene. 2 is a substituted or unsubstituted C2 to C 30 In some embodiments, L is alkenylene. 2 is a substituted or unsubstituted C1-C 30 In some embodiments, L is heteroalkylene. 2 is a substituted or unsubstituted C5-C 25 In some embodiments, L is heteroalkylene. 2 is a substituted or unsubstituted C5-C 12 It is heteroalkylene.

[0444] In some embodiments, L 3 each independently represents -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-C12 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, and in some embodiments, L 3 -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 In some embodiments, L 3 is —O—, —NH—, —S(═O)—, —S(═O)—, 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 to C 15 Cycloalkyl, or substituted or unsubstituted C1-C 12 In some embodiments, L is heterocycloalkyl. 3 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, L 3 is a substituted or unsubstituted C1-C 30 In some embodiments, L is alkylene. 3 is a substituted or unsubstituted C2 to C30 In some embodiments, L is alkenylene. 3 is a substituted or unsubstituted C1-C 30 In some embodiments, L is heteroalkylene. 3 is a substituted or unsubstituted C5-C 25 In some embodiments, L is heteroalkylene. 3 is a substituted or unsubstituted C5-C 12 In some embodiments, L is heteroalkylene. 3 does not exist.

[0445] In some embodiments, L 4 each independently represents -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, or substituted or unsubstituted C1-C 30heteroalkylene, and in some embodiments, L 4 -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 In some embodiments, L 4 is —O—, —NH—, —S(═O)—, —S(═O)—, or —C(═O)—. In some embodiments, L 4 is —C(═O)NH— or —NHC(═O)—. In some embodiments, L 4 is a substituted or unsubstituted C3 to C 15 Cycloalkyl, or substituted or unsubstituted C1-C 12 In some embodiments, L is heterocycloalkyl. 4 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, L 4 is a substituted or unsubstituted C1-C 30 In some embodiments, L is alkylene. 4 is a substituted or unsubstituted C2 to C 30 In some embodiments, L is alkenylene. 4 is a substituted or unsubstituted C1-C 30 In some embodiments, L is heteroalkylene. 4 is a substituted or unsubstituted C5-C 25 In some embodiments, L is heteroalkylene. 4is a substituted or unsubstituted C5-C 12 In some embodiments, L is heteroalkylene. 4 does not exist.

[0446] In some embodiments, L 5 each independently represents -O-, -N...

Claims

1. A (cyclic) peptide having binding ability to ephrin type-A receptor 2 (EphA2), said peptide comprising an amino acid sequence comprising one or several (e.g., 1 to 6) amino acid deletions, substitutions, and / or additions in the amino acid sequence of SEQ ID NO: 1: da-MeF-NL-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. 2. The (cyclic) peptide according to claim 1, wherein 1 to 5 amino acids selected from the group consisting of the third N, the fourth L, the sixth MeF, the tenth T and the eleventh E of SEQ ID NO: 1 are deleted, optionally without further addition and / or substitution.

3. 3. The (cyclic) peptide according to claim 1 or 2, wherein one to several (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 second MeF, the sixth MeF, the eighth V and the eleventh E are substituted.

5. 5. The (cyclic) peptide according to any one of claims 1 to 4, wherein the peptide comprises an amino acid sequence having a deletion of no more than two amino acids in the amino acid sequence SEQ ID NO: 1, optionally without further additions and / or substitutions.

6. 6. The (cyclic) peptide of claim 5, wherein 1 to 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 further addition and / or substitution.

7. A (cyclic) peptide having a binding ability to ephrin type-A receptor 2 (EphA2), the peptide comprising an 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) During the ceremony, X1 is an amino acid; X2 is an amino acid containing an aromatic ring, an N-methylated amino acid thereof, 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 an N-methylated amino acid thereof; 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 a hydrophilic amino acid (e.g., threonine (T) or a mutant thereof); X11 is absent or a hydrophilic amino acid; X12 is cysteine ​​(C) or a mutant thereof, or a (cyclic) peptide, or a pharmaceutically acceptable salt thereof.

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

9. 9. The (cyclic) peptide of claim 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.

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

11. 11. The (cyclic) peptide of claim 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).

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

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

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

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

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

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

18. 18. The (cyclic) peptide according to any one of claims 1 to 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 an unsubstituted phenyl ring of F: (i) -OH, -CN, -C １～３ Alkyl (e.g., —CH ３ a phenyl ring substituted with one or two substituents each independently selected from (ii) -OH, -CN, -C １～３ Alkyl (e.g., —CH ３ a 6-membered heteroaryl ring optionally substituted with one or two substituents each independently selected from and variants thereof in which said F or structural variant thereof 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 four or more carbon atoms in its side chain, including a straight, branched, or cyclic carbon chain), and 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 having a functional side chain (e.g., not glycine)); X6 is the N-methylated amino acid; X7 is an amino acid having either W, Y, or variations thereof, such as a 6-membered aryl or heteroaryl, or a 9- or 10-membered bicyclic aryl or heteroaryl bonded to the alpha carbon through a carbon (e.g., a methylene group), wherein the 6-, 9-, and 10-membered heteroaryl have one heteroatom (e.g., N), and the 6-, 9-, and 10-membered aryl or heteroaryl are not -CH ３ , -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 is 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 having a functional side chain (e.g., not glycine)); 18. The (cyclic) peptide according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein X12 is C or a mutant thereof.

19. 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) During the ceremony, X1 is an amino acid (e.g., a D-amino acid); X2 is an amino acid containing an aromatic ring, an N-methylated amino acid thereof, 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 an N-methylated amino acid thereof; 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); 19. The (cyclic) peptide according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein X12 is C or a mutant thereof.

20. 19. The (cyclic) peptide according to any one of claims 1 to 18, wherein the peptide has an amino acid sequence represented by formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) During the ceremony, X1 is an amino acid (e.g., a D-amino acid); X2 is an amino acid containing an aromatic ring, an N-methylated amino acid thereof, 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 an N-methylated amino acid thereof; 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; 19. The (cyclic) peptide according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein X12 is C or a mutant thereof.

21. 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., linear or branched C １～５ Alkyl-substituted G, C ３～７ G or C substituted with cycloalkyl ３～７ A) substituted with cycloalkyl; X5 is a hydrophilic L-amino acid, wherein the L-amino acid is -NH ２ , -C(O)OH, -NHC(NH)NH ２ , -NHC(O)NH ２ , —C(O)NH ２ , and —NHC(O)CH ３ comprising a functional group selected from X6 is a hydrophilic amino acid, F, Y, W, an N-methylated amino acid thereof, or a variant thereof, wherein the hydrophilic amino acid is -C(O)OH, -C(O)NH ２ , and —NHC(O)CH ３ comprising a functional group selected from X7 is F, W or a variant thereof; X8 is one or two straight or branched chain C １～５ Alkyl-substituted G, C ３～７ Cycloalkyl-substituted G, C ３～７ A substituted with a cycloalkyl, or a hydrophilic L-amino acid, wherein the hydrophilic L-amino acid is -NH ２ , one or more of —OH, —C(O)OH, —NHC(NH)NH ２ , -NHC(O)NH ２ , —C(O)NH ２ , or —NHC(O)CH ３ 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., linear or branched C １～５ Q, S, K, Cit, N, or T optionally substituted with alkyl) or —NHC(NH)NH ２ , -NHC(O)NH ２ , —C(O)NH ２ , or —NHC(O)CH ３ L-amino acids including: X11 is absent, E, Q, R, Cit, K, D, or N, or a mutant thereof; 21. The (cyclic) peptide according to any one of claims 1 to 20, wherein X12 is C or a mutant thereof.

22. 22. The (cyclic) peptide according to any one of claims 1 to 21, wherein the peptide has an amino acid sequence represented by formula (I), or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) During the ceremony, X1 is da, df3CON, dkCOpipzaa, dahp, dDab-NH ２ -Ph3-SO ２ F, dDap-NH ２ -Ph3-SO ２ F, dDap-NH ２ -Ph4-SO ２ F, 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, Qglucamine, 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; 22. The (cyclic) peptide according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein X12 is C, hCys, CdMe, C3RMe, C3SMe, selenocysteine, dc, or penicillamine.

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

24. X7 is W1Me, W1MeCl, W1MeBr, Na1, Na12, W1Et, 3Bzf, 3Bzt, F23dC, W1Me7N, or F23dMe; X8 is V, KCOpipzaa, N, Cit, hCit, KAc, DapAc, OrnAc, A, T, alT, Aib, Alb, Qglucamine, Hgl, Q, E, Hgn, or K; 24. The (cyclic) peptide according to any one of claims 18 to 23, wherein X9 is W1Me, Na11, W1Et, Na121N, 3Bzf, 3Bzt, Na118N, F23dMe, or F23dC.

25. 18. The (cyclic) peptide according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein the peptide comprises an amino acid sequence represented by formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) During the ceremony, 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; 18. The (cyclic) peptide according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein X12 is C or a variant thereof (e.g., C).

26. 18. 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) During the ceremony, 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 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; 18. The (cyclic) peptide according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein X12 is C or a mutant thereof.

27. A (cyclic) peptide having a binding ability to ephrin type A receptor 2 (EphA2), said peptide having 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, (In the formula, 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 an amino acid; X12 is cysteine ​​(C) or a variant thereof; and Optionally, a (cyclic) peptide consisting of a linker connecting said peptide to a payload molecule.

28. The variants of amino acids are selected from amino acids having one, two, or three substituents based on the amino acid, the substituents being independently selected from halogen, -CN, -NH ２ , —NH(C １ ~C ３ alkyl), -N(C １ ~C ３ alkyl) ２ , oxo, —OH, —CO ２ H, -CO ２ -C １ ~C ３ Alkyl, —C(═O)NH ２ , -C(=O)NH(C １ ~C ３ alkyl), -C(=O)N(C １ ~C ３ alkyl) ２ , -S(=O) ２ NH ２ , -S(=O) ２ NH (C １ ~C ３ alkyl), -S(=O) ２ N (C １ ~C ３ alkyl) ２ , C １ ~C ６ Alkyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Alkoxy, C ６ ~C １０ Aryl, C ３ ~C ６ 28. The (cyclic) peptide according to any one of claims 7 to 27, which is selected from cycloalkyl, 6- to 10-membered heterocycloalkyl, and 6- to 10-membered heteroaryl.

29. The variants are selected from amino acids having one or two substituents based on the amino acid, the substituents being independently halogen, —CN, —NH ２ , —NH(C １ ~C ３ alkyl), -N(C １ ~C ３ alkyl) ２ , oxo, —OH, —CO ２ H, -CO ２ -C １ ~C ３ Alkyl, —C(═O)NH ２ , -C(=O)NH(C １ ~C ３ alkyl), -C(=O)N(C １ ~C ３ alkyl) ２ , and C １ ~C ６ 29. The (cyclic) peptide of claim 28, wherein the aryl group is selected from alkyl.

30. 30. The (cyclic) peptide according to any one of claims 7 to 29, wherein the variants are selected from amino acids that have similar hydrophilicity or hydrophobicity compared to the reference amino acid.

31. 30. The (cyclic) peptide according to any one of claims 7 to 29, wherein the variants are selected from amino acids having the same functional group as the reference amino acid, and wherein the variants have a side chain of a different length compared to the reference amino acid.

32. 32. The (cyclic) peptide according to any one of claims 7 to 31, wherein said variant has a molecular weight that does not change by more than 14, 28, 30, 45 or 60 g / mol compared to said reference amino acid.

33. A (cyclic) peptide having binding ability to ephrin type-A receptor 2 (EphA2), said peptide having an amino acid sequence of formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) During the ceremony, X1 is any D- or L-amino acid; X2 is, 【Chemical 1】 wherein: Ring A2 is phenyl or a 6-membered heteroaryl (e.g., heteroaryl with 1 or 2 N); R Ｘ２ are each independently a halogen, —CN, or —NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH,SF ５ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR 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) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, or heterocycloalkyl; wherein said alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally and independently selected from one or more R ＸＡ is replaced by; kx2 is 0, 1, 2 or 3; mx2 is 0, 1, 2, 3 or 4; R ＮＸ２ is H, C １ ~C ６ Alkyl or C １ ~C ６ haloalkyl; ＊ X1 represents the point of attachment to X1; ＊ X3 indicates the point of attachment to X3; X3 is, 【Chemistry 2】 wherein: kx3 is 0, 1, 2 or 3; ＮＸ３ is H, C １ ~C ６ Alkyl or C １ ~C ６ haloalkyl; R Ｘ３ is H, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ aminoalkyl, or C １ ~C ６ is heteroalkyl; ＊ X2 indicates the point of attachment to X2; ＊ X4 indicates the point of attachment to X4; X4 is a hydrophobic amino acid (e.g., an amino acid having four or more carbon atoms in its side chain, including a straight, branched, or cyclic carbon chain), and X4 is C １～３ optionally N-alkylated with an alkyl group; X5 is a hydrophilic L-amino acid, for example, an amino acid having the following structure: 【Chemistry 3】 where: R ＮＸ５ is H, -CN, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ aminoalkyl, or C １ ~C ６ wherein said alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is optionally and independently selected from one or more R ＸＡ is replaced by; R Ｘ５ -CN, -NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH,SF ５ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR 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) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ aminoalkyl, or C １ ~C ６ wherein said alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is optionally and independently selected from one or more R ＸＡ is replaced by; However, RN Ｘ５ and R Ｘ５ At least one of the groups is —OH, —NH ２ and —NH— (e.g., —NH—C(═NH)—NH ２ , —CO—NH ２ , -NH ２ , -COOH, -C(OH)-C ０～６ Alkyl, —NH—CO—C １～６ alkyl); ＊ X4 indicates the point of attachment to X4; ＊ X6 indicates the point of attachment to X6; The X6 is 【Chemistry 4】 (e.g., N, F), where: R ＮＸ６ is H, C １ ~C ６ Alkyl or C １ ~C ６ haloalkyl; R Ｘ６ -CN, -NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH,SF ５ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR 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) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein said alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally and independently selected from one or more R ＸＡ is replaced by; ＊ X5 indicates the point of attachment to X5; ＊ X7 indicates the point of attachment to X7; The X7 is 【Chemistry 5】 wherein: R ＮＸ７ is H, C １ ~C ６ Alkyl or C １ ~C ６ haloalkyl; Ring A7 is aryl or heteroaryl; R Ｘ７ are each independently a halogen, —CN, or —NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH,SF ５ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ -halogen, -S(=O) ２ NR 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) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, or heterocycloalkyl; wherein said alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally and independently selected from one or more R ＸＡ is replaced by; kx7 is 0, 1, 2 or 3; mx7 is 0, 1, 2, 3, 4 or 5; ＊ X6 indicates the point of attachment to X6; ＊ X8 indicates the point of attachment to X8; X8 is an L-amino acid having -H on the α-amino group; The X9 is 【Chemistry 6】 wherein: R ＮＸ９ is H, C １ ~C ６ Alkyl or C １ ~C ６ haloalkyl; Ring A9 is aryl or heteroaryl; R Ｘ９ are each independently a halogen, —CN, or —NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH,SF ５ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR 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) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, or heterocycloalkyl; wherein said alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally and independently selected from one or more R ＸＡ is replaced by; kx9 is 0, 1, 2 or 3; mx9 is 0, 1, 2, 3, 4, or 5; ＊ X8 indicates the point of attachment to X8; ＊ XC represents (i) the point of attachment to X10 or (i) X12 if X10 and X11 are absent; X10 is absent or an L-amino acid; X11 is absent or an L-amino acid; provided that if X10 is absent, then X11 is also absent; X12 is an L-amino acid with a reactive thiol group, such as Cys and Cys variants; Each R ａ are independently １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkyl (cycloalkyl), C １ ~C ６ Alkyl (heterocycloalkyl), C １ ~C ６ Alkyl (aryl), or C １ ~C ６ alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Each R ｂ are independently hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkyl (cycloalkyl), C １ ~C ６ Alkyl (heterocycloalkyl), C １ ~C ６ Alkyl (aryl), or C １ ~C ６ 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 independently hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkyl (cycloalkyl), C １ ~C ６ Alkyl (heterocycloalkyl), C １ ~C ６ Alkyl (aryl), or C １ ~C ６ alkyl(heteroaryl); wherein 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 atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R and R ＸＡ are independently halogen, —CN, —OH, —OC １ ~C ６ Alkyl, SF ５ , -S(=O)C １ ~C ６ Alkyl, —S(═O) ２ C １ ~C ６ Alkyl, —S(═O) ２ NH ２ , -S(=O) ２ -halogen, -S(=O) ２ NHC １ ~C ６ Alkyl, —S(═O) ２ N (C １ ~C ６ alkyl) ２ , -NH ２ , -NHC １ ~C ６ Alkyl, —N(C １ ~C ６ alkyl) ２ , -NR ｂ C (=NR ｂ ) NR ｃ R ｄ , -NHC(=O)OC １ ~C ６ Alkyl, —C(═O)C １ ~C ６ Alkyl, —C(═O)OH, —C(═O)OC １ ~C ６ Alkyl, —C(═O)NH ２ , -C(=O)N(C １ ~C ６ alkyl) ２ , -C(=O)NHC １ ~C ６ Alkyl, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ aminoalkyl, or C １ ~C ６ is heteroalkyl; Optionally, said peptide is linked to the payload molecule via a linker, (cyclic) peptide.

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

35. R ＮＸ７ is H.

36. Each RX ７ are independently —CH ３ 36. The (cyclic) peptide according to any one of claims 33 to 35, wherein mx7 is selected from -ethyl, -Cl and -F, and mx7 is 0, 1 or 2.

37. 34. The (cyclic) peptide of claim 33, wherein X7 is W1Me, Na1, Na12, W1Et, Na121N, 3Bzf, 3Bzt, Na15N, Na14N, Na124N, Na128N, F23dMe, F23dC, W1Me7N, or W1Me7Cl.

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

39. The X9 is 【Chemistry 7】 and each R Ｘ９ are independently —OH, CN, NH ２ , C １ ~C ３ Alkyl, -Cl, -F, -Br, -CNH ２ , and -SO ２ A (cyclic) peptide according to any one of claims 33 to 38, selected from: F.

40. [Chemical 8] teeth, 【Chemistry 9】 40. The (cyclic) peptide according to any one of claims 33 to 39,

41. R Ｘ９ are each independently a halogen, —CN, or —NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR 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 , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ aminoalkyl, or C １ ~C ６ A (cyclic) peptide according to any one of claims 33 to 40, which is heteroalkyl.

42. 39. The (cyclic) peptide of any one of claims 33 to 38, wherein X9 is W1Me, W, Na11, W1Et, Na121N, 3Bzf, 3Bzt, Na14N, Na18N, F23dMe, F23dC, or W1Et.

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

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

45. R Ｘ５ is C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, —C ０～６ Alkylene-NH-C(=NH)-NH ２ , -C ０～６ Alkylene -CO-NH ２ , -C ０～６ Alkylene -COOH, or -NH-CO-C １～６ A (cyclic) peptide according to any one of claims 33 to 44, which is alkyl.

46. X7 is W1Me, W1MeCl, W1MeBr, Na1, Na12, W1Et, 3Bzf, 3Bzt, F23dC, W1Me7N, or F23dMe; X8 is V, KCOpipzaa, Hse, N, Cit, hCit, KAc, DapAc, OrnAc, T, alT, Aib, Alb, Qglucamine, Hgl, E, Hgn, MeF, 3Py6NH2, W1Me, A, Q, or K; 34. The (cyclic) peptide according to any one of claims 27 to 33, wherein X9 is W1Me, Na11, W1Et, Na121N, 3Bzf, 3Bzt, Na118N, F23dMe, or F23dC.

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

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

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

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

51. 51. The (cyclic) peptide of claim 50, wherein the amino acid X1 and cysteine ​​or a variant thereof form a covalent bond.

52. The peptide has the structure of formula (I-1): 【Chemistry 10】 During the ceremony, R １ is NH ２ and OH; R ２ is H or C １～３ selected from the group consisting of alkyl; R ３ is H or C １～３ selected from the group consisting of alkyl; 52. The (cyclic) peptide according to any one of claims 1 to 51, wherein X1 to X11 have the definitions as set out in formula (I).

53. The peptide of formula (I-1) may be a peptide of formula (I-2) 【Chemistry 11】 53. The (cyclic) peptide of claim 52, having the structure:

54. 54. The (cyclic) peptide according to any one of claims 1 to 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 NOs: 1 to 171, or a sequence that has 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 to 171.

55. The (cyclic) peptide according to any one of claims 1 to 54, wherein the peptide or a salt thereof consists of an amino acid sequence selected from SEQ ID NOs: 1 to 171.

56. 56. The (cyclic) peptide of claim 55, wherein the peptide consists of an amino acid sequence selected from SEQ ID NOs: 1-122, 159-163, and 165-171, the peptide has a cyclic structure with a cysteine ​​residue or mutant thereof at the 12th residue, and the amino acid at X1 (e.g., a chloroacetylated amino acid) and the cysteine ​​residue or mutant thereof at the 12th residue form a covalent bond (e.g., by reacting a chloroacetyl group in the amino acid at X1 with the cysteine ​​residue or mutant thereof).

57. 56. The (cyclic) peptide of claim 55, wherein the peptide consists of an amino acid sequence selected from SEQ ID NOs: 123-149 and 164, the peptide has a cyclic structure with a cysteine ​​residue or a variant thereof at the tenth residue, and the amino acid at X1 (e.g., a chloroacetylated amino acid) and the cysteine ​​residue or a variant thereof at the tenth residue form a covalent bond.

58. The peptide exhibited a K ｄ 58. The (cyclic) peptide of any one of claims 1 to 57, having a binding affinity to human EphA2 of 100 nM or less as determined by

59. The peptide exhibited a K ｄ 59. The (cyclic) peptide of claim 58, having a binding affinity for human EphA2 of 1 nM or less as determined by

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

61. 61. The (cyclic) peptide of any one of claims 1 to 60, wherein the peptide interacts with 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.

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

63. The peptide has a plasma half-life (T) 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. １／２ 63. The (cyclic) peptide according to any one of claims 1 to 62, having the following structure:

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

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

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

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

68. 67. The (cyclic) peptide of claim 66, wherein the linker is attached to the eighth amino acid residue or X8.

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

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

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

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

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

74. 73. The (cyclic) peptide of any one of claims 65 to 72, wherein the linker comprises 3 to 30 intervening atoms between the payload molecule and the peptide.

75. 73. The (cyclic) peptide of any one of claims 65 to 72, wherein the linker comprises 6 to 18 intervening atoms between the payload molecule and the peptide.

76. 76. The (cyclic) peptide of claim 74 or 75, wherein the intervening atoms include 1 to 6 nitrogens and 0 to 4 oxygens.

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

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

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

80. The linker has a structure of formula (II-1): 【Chemistry 12】 In the formula, 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) ２ NR Ｌ -, -C(=O)NR Ｌ S (= O) ２ -, -S(=O) ２ NR Ｌ C(=O)-, substituted or unsubstituted C ３ ~C １５ Cycloalkyl, substituted or unsubstituted C １ ~C １２ Heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C １ ~C ３０ Alkylene, substituted or unsubstituted C ２ ~C ３０ Alkenylene, substituted or unsubstituted C ２ ~C ３０ Alkynylene, substituted or unsubstituted C １ ~C ３０ Heteroalkylene, -(C １ ~C ３０ alkylene)-O-, -O-(C １ ~C ３０ alkylene)-, -(C １ ~C ３０ alkylene)-NR Ｌ -, -NR Ｌ -(C １ ~C ３０ alkylene)-, -(C １ ~C ３０ alkylene)-N(R Ｌ ) ２ -, or -N(R Ｌ ) ２ -(C １ ~C ３０ alkylene)-; Each R Ｌ are independently hydrogen, substituted or unsubstituted C １ ~C ４ Alkyl, substituted or unsubstituted C １ ~C ４ Heteroalkyl, substituted or unsubstituted C ２ ~C ６ Alkenyl, substituted or unsubstituted C ２ ~C ５ Alkynyl, substituted or unsubstituted C ３ ~C ８ Cycloalkyl, substituted or unsubstituted C ２ ~C ７ heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 73. The (cyclic) peptide according to any one of claims 65 to 72, wherein n is 1 to 20.

81. The linker comprises a structure of formula (II-1a): 【Chemistry 13】 In the formula, L １ and L ３ each independently represents —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) ２ NR Ｌ -, -C(=O)NR Ｌ S (= O) ２ - or -S(=O) ２ NR Ｌ C(═O)—; L ２ is absent or is a substituted or unsubstituted C １ ~C ３０ Alkylene, or substituted or unsubstituted C １ ~C ３０ 81. The (cyclic) peptide of claim 80, which is a heteroalkylene.

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

83. L ２ is a substituted or unsubstituted C １ ~C ３０ Alkylene, or substituted or unsubstituted C １ ~C ３０ 83. The (cyclic) peptide of claim 81 or 82, which is a heteroalkylene.

84. L ２ is a substituted or unsubstituted C １ ~C １８ Alkylene, or substituted or unsubstituted C １ ~C １８ 83. The (cyclic) peptide of claim 81 or 82, which is a heteroalkylene.

85. L ２ is -OH, -SH, oxo, amino, C １ ~C ６ Alkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ 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 optionally substituted with one or more substituents selected from the group consisting of １ ~C ６ Alkyl is —OH, —SH, oxo, amino, C ６ ~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 85. The (cyclic) peptide of any one of claims 81 to 84, further optionally substituted with one or more substituents selected from:

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

87. The linker is 【Chemistry 14】 【Chemistry 15】 82. The (cyclic) peptide of claim 81 having the structure:

88. The linker is 【Chemistry 16】 82. The (cyclic) peptide of claim 81 having the structure:

89. 89. The (cyclic) peptide of any one of claims 1 to 88, wherein the peptide is of formula (I) and, when the peptide is bound to the human EphA2, amino acid residue X7 is located less than 10 Å from Phe156 of the human EphA2.

90. 90. The (cyclic) peptide of claim 89, wherein amino acid residue X7 is located less than 6 Å from Phe156.

91. 90. The (cyclic) peptide of claim 89, wherein amino acid residue X7 is located less than 4 Å from Phe156.

92. 92. The (cyclic) peptide of any one of claims 1 to 91, wherein the peptide is of formula (I) and, when the peptide is bound to the human EphA2, amino acid residue X9 is located less than 10 Å from Phe156 of the human EphA2.

93. 93. The (cyclic) peptide of claim 92, wherein amino acid residue X9 is located less than 6 Å from Phe156.

94. 94. The (cyclic) peptide of claim 93, wherein amino acid residue X9 is located less than 4 Å from Phe156.

95. 95. The (cyclic) peptide of any one of claims 1 to 94, wherein the peptide is of formula (I) and, when the peptide is bound to the human EphA2, amino acid residue X8 is located less than 10 Å from Phe156 of the human EphA2.

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

277.

97. It has binding ability to ephrin type A receptor 2 (EphA2), and is represented by SEQ ID NO: 1: da-MeF-NL-Hgl-MeF-W1Me-V-W1Me-T-E-C (SEQ ID NO: 1) A (cyclic) peptide which competes for binding to human EphA2 with a peptide having an amino acid sequence containing one or several amino acid deletions, substitutions or additions in the amino acid sequence of the formula (I) or a pharmaceutically acceptable salt thereof.

98. The peptide is a (cyclic) peptide having binding ability to ephrin type-A receptor 2 (EphA2) that competes with a peptide having the structure of formula (I) for binding to human EphA2, or a pharmaceutically acceptable salt thereof, X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) During the ceremony, X1 is an amino acid; X2 is an amino acid containing an aromatic ring, an N-methylated amino acid thereof, 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 an N-methylated amino acid thereof; 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 a hydrophilic amino acid (e.g., threonine (T) or a mutant thereof); X11 is absent or a hydrophilic amino acid; X12 is cysteine ​​(C) or a mutant thereof, or a (cyclic) peptide, or a pharmaceutically acceptable salt thereof.

99. The peptide is a (cyclic) peptide having a binding ability to ephrin type A receptor 2 (EphA2), which 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, During the ceremony, 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 an amino acid; X12 is cysteine ​​(C) or a mutant thereof; The peptide is a (cyclic) peptide, or a pharmaceutically acceptable salt thereof, optionally linked to a payload molecule via a linker.

100. 100. The (cyclic) peptide of 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 Asp53, Met55, Asn57, Met59, Met66, Thr101, Arg103, Phe156, Glu157, Arg159, Val161, Val189, and Ala190.

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

102. The (cyclic) peptide according to any one of claims 97 to 101, wherein said human EphA2 comprises the sequence of SEQ ID NO: 276 or SEQ ID NO:

277.

103. A pharmaceutical composition comprising the peptide or salt thereof according to any one of claims 1 to 102 and a pharmaceutically acceptable excipient or carrier.

104. 104. A conjugate comprising the peptide or salt thereof according to any one of claims 1 to 103 and a substance, wherein the substance is selected from the group consisting of a nucleotide, a small molecule, a medium-sized molecule (e.g., having a molecular weight of about 1,000 to 2,500 Da), a large molecule (e.g., having a molecular weight of more than 2,500 Da), a polymeric compound, a protein, a peptide, a tag, a biological fragment, a carrier comprising a pharmaceutical compound, or a combination thereof.

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

106. 106. The method of claim 105, wherein the disease or disorder is cancer.

107. 107. The method of claim 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.

108. 107. The method of claim 106, wherein the cancer is non-small cell lung cancer (NSCLC).

109. 107. The method of claim 106, wherein the cancer is triple-negative breast cancer.

110. 106. A kit, tester or composition for determining the expression level of EphA2 in a sample, comprising a peptide or a salt thereof according to any one of claims 1 to 102, a conjugate according to claim 103 or a pharmaceutical composition according to claim 104.

111. 111. The kit, tester or composition of claim 110 adapted for use in a method of diagnosing a disease or disorder characterized by overexpression or underexpression of EphA2.

112. 112. The kit, tester or composition of claim 110 or 111, wherein the sample is derived from a subject having a disease or disorder characterized by overexpression or underexpression of EphA2.

113. Use of a peptide or a salt thereof according to any one of claims 1 to 112 in the manufacture of a medicament for diagnosing and / or treating a disease or disorder characterized by overexpression or underexpression of EphA2.

114. A peptide or salt thereof according to any one of claims 1 to 113 for use in diagnosing and / or treating a disease or disorder characterised by overexpression or underexpression of EphA2.

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