Peptide compositions targeting glypican-3 and uses thereof

Abstract

The present technology generally relates to peptides that bind to phosphatidylinositol proteoglycan 3 (GPC3), to peptides that bind to the GPC3, and to compositions comprising such peptides.

Description

This invention relates generally to peptides bound to phosphatidylinositol proteoglycan 3 (GPC3), peptides bound to GPC3, and compositions comprising such peptides. Abstract

Claims

CLAIMSWhat is claimed is:1 . A peptide that has avidity for Glypican 3 (GPC3), or a pharmaceutically acceptable salt thereof, wherein the peptide comprises an amino acid sequence including deletion, substitution, and / or addition of one or several (e.g., 1-6) amino acids in the amino acid sequence of SEQ ID NO: 1 :MeK-Mel-D-MeQ-F4COO-l-l-Y-MeNal27N-G-3Py6Ph-MeC (SEQ ID NO: 1), wherein the peptide consists of 10 to 12 amino acid residues.

2. The peptide of claim 1 , or a pharmaceutically acceptable salt thereof, wherein 1 , 2, 3, 4 or 5 amino acids are added.

3. The peptide of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the peptide is a cyclic peptide.

4. A peptide that has avidity for Glypican 3 (GPC3), or a pharmaceutically acceptable salt thereof, wherein the peptide comprises an amino acid sequence of Formula (I),X1 -X2-X3-X4-X5-X6-X7-X8-X9-X10-X11 -X12Formula (I) wherein,XI is any amino acid;X2 is any amino acid;X3 is any amino acid;X4 is any amino acid;X5 is an amino acid comprising an aromatic ring (e.g., \N, F, Y, or a variant thereof), cycloalkyl, or heterocycloalkyl group, or X5 is a peptoid (e.g., Cha4cH, Cha4tH, A1mor, Atp, Cha4cOMe);X6 is a hydrophobic amino acid, a hydrophilic amino acid, or a polar amino acid wherein the polar amino acid has a substituted side chain;X7 is a hydrophobic amino acid comprising a Ci-Cs alkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl are each independently, optionally substituted (e.g., X7 is I, Eva, all, TMe, SMe, Gcpr, Gcpe, Gthp, dMeS, TdMe, or Cbg);X8 is a A, I, L, V, Y or F, or a variant thereof;X9 is an N-alky lated amino acid comprising an aromatic ring;X10 is G, A, or a D-amino acid (e.g, da, ds, de, or dp);XI I is an amino acid comprising an aromatic ring (e.g., F, Y, or a variant thereof); and, X12 is N-alkylated cysteine (e.g., MeC).

5. The peptide of claim 4, or a pharmaceutically acceptable salt thereof, wherein X1 is an N-methylated amino acid.

6. The peptide of claim 4 or 5, or a pharmaceutically acceptable salt thereof, wherein X1 is an N-methylated amino acid comprising a polar side chain (e.g., MeK, MeQ, or a variant thereof).

7. The peptide of any one of claims 4 to 6, or a pharmaceutically acceptable salt thereof, wherein X2 is a L-amino acid.

8. The peptide of claim 7, or a pharmaceutically acceptable salt thereof, wherein X2 is a N-methylated amino acid.

9. The peptide of any one of claims 4 to 8, or a pharmaceutically acceptable salt thereof, wherein X3 is a polar and / or an L-amino acid.

10. The peptide of claim 9, or a pharmaceutically acceptable salt thereof, wherein X3 is an amino acid comprising a hydrophilic side chain (e.g., D, K, Q, or a variant thereof) or an N-methylated variant thereof.11 . The peptide of any one of claims 4 to 10, or a pharmaceutically acceptable salt thereof, wherein X4 is a polar and / or an L-amino acid.

12. The peptide of claim 11 , or a pharmaceutically acceptable salt thereof, wherein X4 is an N-methylated amino acid, a polar amino acid (e.g., D, K, Q, S, or a variant thereof), or peptoid (e.g. EtG, MeeG, CmG, CmpG CrmG CeG CrpG).

13. The peptide of any one of claims 4 to 12, or a pharmaceutically acceptable salt thereof, wherein X5 has an aromatic side chain, such as F, Y, or a variant thereof.

14. The peptide of claim 13, or a pharmaceutically acceptable salt thereof, wherein X5 is:F, or a variant thereof comprising a phenyl, pyridinyl, or naphthalyl, wherein said phenyl, pyridinyl, or naphthalyl is optionally substituted with one or more substituents each independently selected from halogen, -Ci.3alkyl, -OH, -NH2, -CN, -C(=O)OH, -C(=O)NH2, -NHC(=O)CH3, -Ci.3alkylene- C(=O)OH, -Ci-3alkylene-C(=O)NH2, -O-Ci-3alkylene-C(=O)OH, -O-Ci-3alkylene-C(=O)NH2, -Ci-3alkylene- C(=O)-5- to 6-membered heterocycloalkylene-Ci-3alkylene-C(=O)OH, -O-Ci-3alkylene-C(=O)- 5- to 6- membered heterocycloalkylene-Ci-3alkylene-C(=O)OH, -Ci-3alkylene-NHC(=O)- 5- to 6-membered heterocycloalkylene-Ci-3alkylene-C(=O)OH, -O-Ci-3alkylene-NHC(=O)- 5- to 6-membered heterocycloalkylene-Ci-3alkylene-C(=O)OH, and -NH-Ci-3alkylene-C(=O)OH; orY, or a variant thereof comprising a hydroxyphenyl, wherein the hydrogen atom in hydroxyphenyl of Y or of the variant is optionally substituted with one or more substituents selected from -Ci-3alkyl, , and -Ci-3alkylene-C(=O)OH.

15. The peptide of any one of claims 4 to 14, or a pharmaceutically acceptable salt thereof, wherein X6 is an aliphatic amino acid (e.g., V, L, I, A, G, or a variant thereof), a hydrophilic amino acid (e.g., D, E, or a variant thereof), threonine (T) or a variant thereof (e.g., O-methyl threonine (TMe)), serine (S), or methionine (M).

16. The peptide of any one of claim 4 to 15, or a pharmaceutically acceptable salt thereof, wherein X7 is anamino acid comprising a branched alkyl side chain, a Ca-scycloalkyl side chain, or a 3- to 5- membered heterocycloalkyl side chain, or an N-methylated variant thereof.

17. The peptide of claim 16, or a pharmaceutically acceptable salt thereof, wherein the branched alkyl side chain comprises 3-5 carbon atoms.

18. The peptide of claim 16 or 17, or a pharmaceutically acceptable salt thereof, wherein the alkyl, cycloalkyl, or heterocycloalkyl side chain is optionally substituted with -O-Ci-Ce alkyl.

19. The peptide of any one of claim 4 to 18, or a pharmaceutically acceptable salt thereof, wherein X8 is: an aliphatic amino acid (e.g., A, I, L, or V);Y, or a variant thereof comprising a hydroxyphenyl ring, wherein the hydroxyphenyl ring of Y or of the variant is optionally substituted with one or more substituents selected from halogen, -Ci-salkyl, -OH, -C(=O)OH, -O-CH3, -Ci-3alkylene-C(=O)OH, -Ci-3alkylene-C(=O)- 5- to 6-membered heterocycloalkylene-Ci-3alkylene-C(=O)OH, and -Ci-3alkylene-NHC(=O)- 5- to 6-membered heterocycloalkylene-Ci-3alkylene-C(=O)OH; orF, or a variant thereof comprising a phenyl, pyridinyl, or indazolyl, wherein the phenyl of F or the phenyl, pyridinyl, or indazolyl of the variant is optionally substituted with one or more substituents each independently selected from halogen, -Ci-salkyl, -OH, -C(=O)OH, -C(=O)NH2, -NHC(=O)NH2, -Ci. 3alkylene-C(NH2)-COOH, -NH-CO-CH3, -NH-Ci-3alkylene-NH2, -C(=O)-N(CH2)2, -S(=O)2-CH3, -Ci. 3alkylene-NH-C(=O)- 5- to 6-membered heterocycloalkylene-Ci-3alkylene-C(=O)OH, and -O-C1- 3alkylene-NH-C(=O)- 5- to 6-membered heterocycloalkylene-Ci-3alkylene-C(=O)OH.

20. The peptide of any one of claim 4 to 19, or a pharmaceutically acceptable salt thereof, wherein X9 is an N-methyl aromatic amino acid, optionally a bicyclic aromatic amino acid.21 . The peptide of claim 20, or a pharmaceutically acceptable salt thereof, wherein the N-methyl aromatic amino acid is:N-methyl monocyclic aromatic amino acid comprising a phenyl or pyridinyl optionally substituted with one or more substituents each independently selected from halogen, -Ci-salkyl, and trifluoromethyl; orN-methyl bicyclic aromatic amino acid comprising a naphthalyl, quinolyl, or indazolyl optionally substituted with one or more substituents each independently selected from H or Ci-3alkyl .

22. The peptide of any one of claims 4 to 21, or a pharmaceutically acceptable salt thereof, wherein X10 is G or a D-amino acid (e.g., da, ds, de, or dp).

23. The peptide of any one of claims 4 to 22, or a pharmaceutically acceptable salt thereof, wherein X11 is F or a variant thereof, or an amino acid comprising -Ci-6alkylene-phenyl.

24. The peptide of claim 23, or a pharmaceutically acceptable salt thereof, wherein F or the variant thereof is:F, or a variant thereof comprising a phenyl, or pyridinyl, optionally substituted with one or more substituents each independently selected from phenyl, -O-phenyl, -O-Ci-salkylene-phenyl, pyridinyl, imidazolyl, pyrazolyl, N-Ci-salkylene pyrazolyl, N-Ci-3alkylene(-O-Ci-3alkyl) pyrazolyl, pyranyl, tetrahydropyranyl, piperidinyl, N-Ci-3alkylene-C(=O)-piperidinyl.

25. The peptide of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein the peptide has an amino acid sequence according to Formula (I), or a pharmaceutically acceptable salt thereof,X1 -X2-X3-X4-X5-X6-X7-X8-X9-X10-X11 -X12Formula (I) wherein,X1 is I, R, Cit, F4G, 4Py, 3Py, KCOpipzaa, V, Eva, Q, E, Mel, Ahp, F4COO, KCOpip4COO, MeQdMe, MeA, MeSMe, MeG, MeV, MeHseMe, Alb, MeT, all, TMe, MeKCOpipzaa, MeQ, Hpr, MeTMe, MeDapCOpipzaa, MeK, MeKAc, MeK(de), MeK(H), MeK(df), or MeK(datb);X2 is I, K, Cit, F4G, 4Py, 3Py, KCOpipzetOH, V, KCOpipzaa, Eva, Q, E, S, Ahp, F4COO, KCOpip4COO, MeQdMe, MeA, MeSMe, MeG, Mel, MeV, MeL, HseMe, MeY, Me3Py, MeHseMe, MeKAc, all, TMe MeKCOpipzaa, MeQ, Hpr, MeTMe, or MeDapCOpipzaaa;X3 is D, Har, KCOpipzetOH, Cit, KCOmeglumine, KCOpipzaa, A4paa, Q, A, E, MeD, S, N, Hgl, F4COO, KCOpip4COO, KAc, Hgn, MeY, or DapCOpipzaa;X4 is D, Har, KCOpipzetOH, KCOmeglumine, KCOpipzaa, A4paa, Q, A, E, MeD, S, N, Hgl, F4COO, KCOpip4COO, dd, MeQ, MeQdMe, MeA, MeSMe, MeG, EtG, MeeG, CmG, CmpG, CrmG, CeG, CrpG, MeK, MeKAc, MeHgl, Hgn, MeDapCOpipzaa, MeKCOpipzaa, Medd, Cit, MeCit, MeN, MeS, MeE, MeY, W5N or Mae4paa;X5 is Y, F3G, 3Py6COO,4Py2NH2, 3Py5COO, F3COO, 3Py6NHAc, F, F4C, F4OMe, F4COO, Nal2, F3aao, F4aa, F4aao, 3Py6Nhaa, 5Pdo, F3CON, F4F, F4OEt, F4Me, F4CON, F4CONPEG4Me, F3OMe, Yae, YaeCOpipzaa, F4aaopipzaa, 4Pdo, 3Py6CON, Atp, Cha4cH, Cha4tH, Cha4cOMe, A1mor, or F4amC0pipzaa;X6 is I, V, Eva, Chg, Tbg, A, L, Ahp, F4COO, Gcpr, Gcpe, all, Cle , S3REt, TMe, Acpr, Cba, Gthp, NleCOO, NleOH, P, Atb, Nva, Nle, N, DapAc, Abu, Nmm, Ndm, Ncit, Cit, SMe, HseMe, HseEt, HseiPr, dMeS, TdMe, Cbg, NvaOMe, SiPr, Spr, NleOme, Sbu, Scbm, Scpe, AhpOMe, HseBu, Spent or Hsecpe;X7 is I, Eva, all, TMe, SMe, Gcpr, Gcpe, Gthp, dMeS, TdMe, or Cbg;X8 is A, I, L, V, Y, F4OMe, F4COO, F4OEt, F4u, F4Me, F4CONdMe, F4CON, F4ms, F4CONPEG4Me, F34dOMe, F3OMe, F3C, F3CON, F3CONdMe, 3Py6CON, Yae, YaeCOpipzaa, 5lnda, F3aao, F3aa, 3Py6Nhae, 3Py6NHAc, 3Py6OMe, F4aaopipzaa, or F4amC0pipzaa;X9 is MeNal2, MeNal27N, MeF34diox, MeF34dOMe, MeF4T, MeY, MeWI Me, MeW7N, MeF3C4Me, or MeF3Me4C;X10 is G, A, or a D-amino acid (e.g., da, ds, de, or dp);X11 is Bph, 3Py6Ph, F41 Me4Pyz, F43Pyz, F44Pyz, F41 Pyz, F41 Me3Pyz, F41 Et4Pyz, F41 MeOe4Pyz, F41 MeOp4Pyz, F44thp, F4Ac4pip, PhNva, PhNIe, Yph, Ybn, F4tb, F4oPr, or F4C0NdMe; andX12 is MeC.

26. A peptide having avidity for Glypican 3 (GPC3), or a pharmaceutically acceptable salt thereof, wherein the peptide has an amino acid sequence of Formula (I),X1 -X2-X3-X4-X5-X6-X7-X8-X9-X10-X11 -X12Formula (I) wherein,X1 is any amino acid;X2 is any amino acid;X3 is any amino acid;X4 is any amino acid;wherein:Rn5is hydrogen or C1-3 alkyl; ring A5 is an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; each RX5is independently C^alkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, Ci-eaminoalkyl, Ci-eheteroalkyl, C2-6alkenyl, 02-ealkynyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Ra, -S(=0)2Ra, - S(=O)2NRcRd, -S(=O)(=NRa)Ra, -N=S(=O)NRcRd, -NRaS(=O)2Ra, amidinyl, -NRaC(=NH)NRcRd, -NRaS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)NRcRd, - NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), - P(=O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -LX5-heterocycloalkyl, -LX5-cycloalkyl, - LX5-aryl, or -LX5-heteroaryl, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more RX5a; or two RX5are taken together to form =0, =S, or =N(Ra);LX5is Ci-6alkylene, Ci-sheteroalkylene, -0-, -S-, or -NRa- , wherein the alkylene and heteroalkylene is optionally substituted with one or more RX5a; kx5 is O, 1, 2, or 3; mx5 is O, 1 , 2, 3, 4, or 5;*X4 represents the point of attachment to X4; and*X6 represents the point of attachment to X6;,herein;Rn6is hydrogen or C1-3 alkyl;RX6is Ci-ealkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, Ci-eaminoalkyl, Ci-eheteroalkyl, C2-ealkenyl, C2- ealkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -LX6-heterocycloalkyl, -LX6-cycloalkyl, - LX6-aryl, or -LX6-heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more RX6a; orRn6and Rx6are taken together with the intervening atoms to form a 5- to 6- membered heterocycloalkyl, which is optionally substituted with one or more RX6a;LX6is Ci-6alkylene, Ci-eheteroalkylene, -O-, -S-, or -NRa-, wherein the alkylene and heteroalkylene is optionally substituted with one or more RX6a;*X5 represents the point of attachment to X5; and*X7 represents the point of attachment to X7;, wherein:Rn7is hydrogen or C1-3 alkyl ;RX7is Ci-ealkyl, C-i-ehaloalkyl, Ci-ehydroxyalkyl, Ci-eaminoalkyl, Ci-eheteroalkyl, C2-6alkenyl, C2- ealkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more RX7a;*X6 represents the point of attachment to X6; and*X8 represents the point of attachment to X8;Rn8is hydrogen or Ci-salkyl; ring A8 is an aryl or heteroaryl;each RX8is independently Ci-ealkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, Ci-eaminoalkyl, Ci-eheteroalkyl, C2-ealkenyl, C2-ealkynyl, halogen, -CN, -NO2, -0Ra, -SRa, -SF5, -NRcRd, -S(=0)Ra, -S(=0)2Ra, - S(=0)2RcRd, -S(=0)(=NRa)Ra, -N=S(=O) RcRd, -NRaS(=0)2Ra, amidinyl, -NRaC(=NH)NRcRd, - NRaS(=0)2RcRd, -C(=0)Ra, -C(=0)0Ra, -0C(=0)Ra, -0C(=0)0Ra, -0C(=0)NRcRd, - NRaC(=0)Ra, -NRaC(=0)0Ra, -NRaC(=0)NRcRd, -C(=0)NRcRd, -P(=0)(0Rc)(0Rd), - P(=0)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -LX8-heterocycloalkyl, -LX8-cycloalkyl, - LX8-aryl, or -LX8-heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more RX8a; or two RX8are taken together to form =0, =S, or =N(Ra);LX8is Ci-ealkylene, Ci-eheteroalkylene, -0-, -S-, or -NRa-, wherein the alkylene and heteroalkylene is optionally substituted with one or more RX8a; kx8 is O, 1, 2, or 3; mx8 is O, 1 , 2, 3, 4, or 5;*X7 represents the point of attachment to X7; and*X9 represents the point of attachment to X9;wherein:Rn9is hydrogen or C1-3 alkyl; ring A9 is an aryl or heteroaryl; each RX9is independently Ci-ealkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, Ci-eaminoalkyl, Ci-eheteroalkyl, C2-6alkenyl, C2-ealkynyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, or -NRcRd, wherein each of the alkyl, heteroalkyl, alkenyl, and alkynyl is optionally substituted with one or more RX9a; or two RX9are taken together to form =0, =S, or =N(Ra); kx9 is O, 1, 2, or 3; mx9 is O, 1 , 2, 3, 4, or 5;*X8 represents the point of attachment to X8; and*X10 represents the point of attachment to X10;X10 is glycine or a D-amino acid (e.g., da, ds, de, or dp);wherein:Rn11is hydrogen or C1-3 alkyl; ring A11 is an aryl or heteroaryl; each RX11is independently Ci-ealkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, Ci-eaminoalkyl, C1- 6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2RcRd, -S(=O)(=NRa)Ra, -N=S(=O)RcRd, -NRaS(=O)2Ra, amidinyl, -NRaC(=NH)NRcRd, - NRaS(=O)2RcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)NRcRd, - NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), - P(=O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -LX11-heterocycloalkyl, -Lx11-cycloalkyl, -Lx11-aryl, or -LX11-heteroaryl, wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more Rx11a; or two RX11are taken together to form =0, =S, or =N(Ra);LX11is Ci-6alkylene, Ci-sheteroalkylene, -0-, -S-, or -NRa-, wherein the alkylene and heteroalkylene is optionally substituted with one or more Rx11a; kx11 is O, 1 , 2, 3, 4, or 5; mx11 is O, 1 , 2, 3, 4, or 5;*X10 represents the point of attachment to X10; and,*X12 represents the point of attachment to X12;X12 is N-alkylated cysteine; each of RX5a, RX6a, RX7a, RX8a, RX9a, and Rx11ais independently halogen, C1-6 alkyl, Ci-Cehaloalkyl, C1- Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -CN, -N02, -0Ra, - SRa, -NRcRd, -S(=0)Ra, -S(=0)2Ra, -SP5, -S(=0)2NRcRd, -S(=0)(=NRa)Ra, -N=S(=0)RcRd, - NRaS(=0)2Ra, amidinyl, -NRaC(=NH)(NRa)2, -NRaS(=0)2NRcRd, -C(=0)Ra, -C(=0)0Ra, -0C(=0)Ra, -0C(=0)0Ra, -0C(=0)NRcRd, -NRaC(=0)Ra, -NRaC(=0)0Ra, -NRaC(=0)NRcRd, -C(=0)NRcRd, - P(=0)(0Rc)(0Rd), -P(=0)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =0, =S, or =N(Ra), wherein each of the alkyl, heteroalkyl, alkenyl, and alkynyl is optionally substituted with one or more Re. each Rais independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-i-Cealkyl (cycloalkyl), Ci-C6alkyl(heterocycloalkyl), Ci-C6alkyl(aryl), or Ci-Cealkyl (heteroaryl), wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re;each Reis independently halogen, -CN, -OH, -O-Ci-Cealkyl, -SF5, -S(=O)Ci-Cealkyl, -S(=O)2Ci-Cealkyl, - S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHCi-C6alkyl, -S(=O)2N(Ci-C6alkyl)2, -NH2, -NHCi-C6alkyl, - N(Ci-C6alkyl)2, -NHC(=NH)NH2, -NHC(=O)OCi-C6alkyl, -C(=O)Ci-C6alkyl, -C(=O)OH, Ci-C6alkyl- C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)N(Ci-C6alkyl)2, -C(=O)NHCi-C6alkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; or two Reare taken together to form =0; and each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-Cealkyl(cycloalkyl), Ci-Cealkyl(heterocycloalkyl), Ci-Cealkyl(aryl), orCi-Cealkyl (heteroaryl), wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more Re.

27. The peptide of claim 26, or a pharmaceutically acceptable salt thereof, wherein X1 is an N-alkylated amino acid.

28. The peptide of claim 26 or 27, or a pharmaceutically acceptable salt thereof, whereinRn1is hydrogen or C1-3 alkyl;RX1is hydrogen, Ci-ealkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, Ci-eaminoalkyl, Ci-eheteroalkyl, C2-6alkenyl, C2-6alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -Lx1-heterocycloalkyl, -Lx1-cycloalkyl, -LX1- aryl, or -Lx1-heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more Rx1a;RX1’ is hydrogen or Ci-ealkyl, wherein the alkyl is optionally substituted with one or more Rx1a; orRn1and RX1’ are taken together with the intervening atoms to form a 5- to 6- membered heterocycloalkyl, which is optionally substituted with one or more Rx1a;LX1is Ci-6alkylene, Ci-eheteroalkylene, -O-, -S-, or -NRa-, wherein the alkylene and heteroalkylene is optionally substituted with one or more Rx1a; each Rx1ais independently halogen, C1-6 alkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, C1- Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, - SF5, -S(=O)2NRcRd, -S(=O)(=NRa)Ra, -N=S(=O)RcRd, -NRaS(=O)2Ra, amidinyl, -NRaC(=NH)(NRa)2, - NRaS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl,cycloalkyl, heterocycloalkyl, =0, =S, or =N(Ra), wherein each of the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, alkenyl, and alkynyl is optionally substituted with one or more R-*X12 represents the point of attachment to X12; and*X2 represents the point of attachment to X2.

29. The peptide of any one of claims 26 to 28, or a pharmaceutically acceptable salt thereof, wherein:Rn1is hydrogen or methyl;RX1is hydrogen, Cvealkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, Ci-eaminoalkyl, Ci-eheteroalkyl, -Lx1-5-6 membered heterocycloalkyl, -Lx1-C4-6cycloalkyl, -l_x1-C6-ioaryl, or -Lx1-5-10 membered heteroaryl, wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more Rx1a;RX1’ is hydrogen or methyl; orRn1and RX1’ are taken together with the intervening atoms to form a 5- to 6- membered heterocycloalkyl, which is optionally substituted with one or more Rx1a;LX1is Ci-6alkylene or Ci-6heteroalkylene, wherein the alkylene and heteroalkylene is optionally substituted with one or more Rx1a; each Rx1ais independently halogen, C1-6 alkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci- Ceheteroalkyl, C2-C6alkenyl, C2-Cealkynyl, -CN, -NO2, -0Ra, -SRa, -NRcRd, -S(=0)Ra, -S(=0)2Ra, - SF5, -S(=0)2NRcRd, -S(=0)(=NRa)Ra, -N=S(=0)RcRd, -NRaS(=0)2Ra, amidinyl, -NRaC(=NH)(NRa)2, - NRaS(=0)2NRcRd, -C(=0)Ra, -C(=0)0Ra, -0C(=0)Ra, -0C(=0)0Ra, -0C(=0)NRcRd, -NRaC(=0)Ra, -NRaC(=0)0Ra, -NRaC(=0)NRcRd, -C(=0)NRcRd, -P(=0)(0Rc)(0Rd), -P(=0)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =0, =S, or =N(Ra), wherein each of the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, alkenyl, and alkynyl is optionally substituted with one or more Re;*X12 represents the point of attachment to X12; and*X2 represents the point of attachment to X2.

30. The peptide of claim 28 or 29, or a pharmaceutically acceptable salt thereof, wherein:RX1is hydrogen, Ci-ealkyl, Ci-eheteroalkyl, -Lx1-piperidinyl, -Lx1-piperazinyl, -Lx1-phenyl, or -Lx1-pyridinyl, wherein each of the alkyl, heteroalkyl, phenyl, pyridinyl, piperidinyl, and piperazinyl is optionally substituted with one or more Rx1a.31 . The peptide of any one of claims 28 to 30, or a pharmaceutically acceptable salt thereof, wherein:each Rx1ais independently halogen, C1-6 alkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci- C6heteroalkyl, -CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRaS(=O)2Ra, -NRaC(=NH)(NRa)2, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)NRcRd, - NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, or =0, wherein each of the alkyl and heteroalkyl is optionally substituted with one or more Re.

32. The peptide of any one of claims 26 to 31 , or a pharmaceutically acceptable salt thereof, wherein X2 is an N-alkylated amino acid.

33. The peptide of any one of claims 26 to 32, or a pharmaceutically acceptable salt thereof, wherein:wherein,Rn2is hydrogen or C1-3 alkyl, wherein the alkyl is optionally substituted with one or more RX2a;RX2is hydrogen, Ci-ealkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, Ci-eaminoalkyl, Ci-eheteroalkyl, C2- ealkenyl, C2-ealkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -LX2-heterocycloalkyl, -LX2- cycloalkyl, -L^-aryl, or -LX2-heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more RX2a;RX2’ is hydrogen or Ci-ealkyl, wherein the alkyl is optionally substituted with one or more RX2a; or Rn2and RX2’ are taken together with the intervening atoms to form a 5- to 6- membered heterocycloalkyl, which is optionally substituted with one or more RX2a;LX2is Ci-6alkylene, Ci-eheteroalkylene, -0-, -S-, or -NRa-, wherein the alkylene and heteroalkylene is optionally substituted with one or more RX2a; each RX2ais independently halogen, C1-6 alkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -CN, -N02, -0Ra, -SRa, -NRcRd, -S(=O)Ra, - S(=O)2Ra, -SF5, -S(=O)2NRcRd, -S(=O)(=NRa)Ra, -N=S(=O)RcRd, -NRaS(=O)2Ra, amidinyl, - NRaC(=NH)(NRa)2, -NRaS(=O)2NRcRd, -C(=0)Ra, -C(=0)0Ra, -0C(=0)Ra, -0C(=0)0Ra, - 0C(=0)NRcRd, -NRaC(=0)Ra, -NRaC(=0)0Ra, -NRaC(=0)NRcRd, -C(=0)NRcRd, - P(=0)(0Rc)(0Rd), -P(=0)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =0, =S, =N(Ra), aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein each of the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, alkenyl, and alkynyl is optionally substituted with one or more Re;*X1 represents the point of attachment to X1 ; and*X3 represents the point of attachment to X3.

34. The peptide of any one of claims 26 to 33, or a pharmaceutically acceptable salt thereof, whereinwherein:Rn2is hydrogen or methyl;RX2is hydrogen, Ci-ealkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, Ci-eaminoalkyl, Ci-eheteroalkyl, -L^-S-S membered heterocycloalkyl, -LX2-C4-6cycloalkyl, -LX2-C6-ioaryl, or -L^-S-W membered heteroaryl, wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more RX2a;RX2’ is hydrogen or methyl; orRn2and RX2’ are taken together with the intervening atoms to form a 5- to 6- membered heterocycloalkyl, which is optionally substituted with one or more RX2a;LX2is Ci-6alkylene or Ci-6heteroalkylene, wherein the alkylene and heteroalkylene is optionally substituted with one or more RX2a; each RX2ais independently halogen, C1-6 alkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Ra, - S(=O)2Ra, -SF5, -S(=O)2NRcRd, -S(=O)(=NRa)Ra, -N=S(=O)RcRd, -NRaS(=O)2Ra, amidinyl, - NRaC(=NH)(NRa)2, -NRaS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OC(=O)ORa, - OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =0, =S, or =N(Ra), wherein each of the alkyl, heteroalkyl, alkenyl, and alkynyl is optionally substituted with one or more Re;*X1 represents the point of attachment to X1 ; and*X3 represents the point of attachment to X3.

35. The peptide of claim 33 or 34, or a pharmaceutically acceptable salt thereof, whereinRX2is hydrogen, Ci-ealkyl, Ci-eheteroalkyl, -LX2-piperidinyl, L^-piperazinyl, -LX2-phenyl, or -LX2-pyridinyl, wherein each of the alkyl, heteroalkyl, phenyl, pyridinyl, piperidinyl, and piperazinyl is optionally substituted with one or more RX2a.

36. The peptide of any one of claims 33 to 35, or a pharmaceutically acceptable salt thereof, wherein each RX2ais independently halogen, C1-6 alkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, C1-C6heteroalkyl, -CN, -N02, -0Ra, -SRa, -NRcRd, -S(=0)Ra, -S(=0)2Ra, -S(=0)2NRcRd, -NRaS(=0)2Ra, -NRaC(=NH)(NRa)2, -C(=0)Ra, -C(=0)0Ra, -0C(=0)Ra, -0C(=0)0Ra, -0C(=0)NRcRd, - NRaC(=0)Ra, -NRaC(=0)0Ra, -NRaC(=0)NRcRd, -C(=0)NRcRd, or =0, wherein each of the alkyl and heteroalkyl is optionally substituted with one or more Re.

37. The peptide of any one of claims 26 to 36, or a pharmaceutically acceptable salt thereof, whereinwherein:Rn3is hydrogen or Ci-salkyl, wherein the alkyl is optionally substituted with one or more RX3a;RX3is hydrogen, Ci-ealkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, Ci-eaminoalkyl, Ci-eheteroalkyl, C2-ealkenyl, C2-6alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -LX3-heterocycloalkyl, -LX3-cycloalkyl, -LX3- aryl, or -LX3-heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more RX3a;RX3’ is hydrogen or Ci-ealkyl, wherein the alkyl is optionally substituted with one or more RX3a; orRn3and RX3’ are taken together with the intervening atoms to form a 5- to 6- membered heterocycloalkyl, which is optionally substituted with one or more RX3a;LX3is Ci-6alkylene, Ci-eheteroalkylene, -O-, -S-, or -NRa-, wherein the alkylene and heteroalkylene is optionally substituted with one or more RX3a; each RX3ais independently halogen, Ci-ealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci- Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, - SF5, -S(=O)2NRcRd, -S(=O)(=NRa)Ra, -N=S(=O)RcRd, -NRaS(=O)2Ra, amidinyl, -NRaC(=NH)(NRa)2, - NRaS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =0, =S, or =N(Ra), wherein each of the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, alkenyl, and alkynyl is optionally substituted with one or more Re;*X2 represents the point of attachment to X2; and*X4 represents the point of attachment to X4.

38. The peptide of any one of claims 26 to 37, or a pharmaceutically acceptable salt thereof, whereinwherein:Rn3is hydrogen or methyl;RX3is Ci-ealkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, Ci-eaminoalkyl, Ci-eheteroalkyl, -LX3-5-6 membered heterocycloalkyl, -LX3-C3-6cycloalkyl, -LX3-C6-ioaryl, or -LX3-5-10 membered heteroaryl, wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more RX3a;LX3is Ci-6alkylene or Ci-sheteroalkylene, wherein the alkylene and heteroalkylene is optionally substituted with one or more RX3a; each RX3ais independently halogen, C1-6 alkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci- Ceheteroalkyl, C2-C6alkenyl, C2-Cealkynyl, -CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, - SF5, -S(=O)2NRcRd, -S(=O)(=NRa)Ra, -N=S(=O)RcRd, -NRaS(=O)2Ra, amidinyl, -NRaC(=NH)(NRa)2, - NRaS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =0, =S, or =N(Ra), wherein each of the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, alkenyl, and alkynyl is optionally substituted with one or more Re;*X2 represents the point of attachment to X2; and*X4 represents the point of attachment to X4.

39. The peptide of claim 37 to 38, or a pharmaceutically acceptable salt thereof, whereinRX3is Ci-ealkyl, Ci-eheteroalkyl, -LX3-piperidinyl, LX3-piperazinyl, -LX3-phenyl, or -LX3-pyridinyl, wherein each of the alkyl, heteroalkyl, phenyl, pyridinyl, piperidinyl, and piperazinyl is optionally substituted with one or more RX2a.

40. The peptide of any one of claims 37 to 39, or a pharmaceutically acceptable salt thereof, wherein each RX3ais independently halogen, Ci-ealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, C1-C6heteroalkyl, -CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRaS(=O)2Ra, -NRaC(=NH)(NRa)2, -C(=0)Ra, -C(=0)0Ra, -0C(=0)Ra, -0C(=0)0Ra, -0C(=0)NRcRd, - NRaC(=0)Ra, -NRaC(=0)0Ra, -NRaC(=0)NRcRd, -C(=0)NRcRd, or =0, wherein each of the alkyl and heteroalkyl is optionally substituted with one or more Re.41 . The peptide of any one of claims 26 to 40, or a pharmaceutically acceptable salt thereof, wherein X4 is an N-alkylated amino acid.

42. The peptide of any one of claims 26 to 40, or a pharmaceutically acceptable salt thereof, wherein X4 is a peptoid.

43. The peptide of any one of claims 26 to 42, or a pharmaceutically acceptable salt thereof, whereinwherein:Rn4is hydrogen or C1-3 alkyl, wherein the alkyl is optionally substituted with one or more RX4a;RX4is hydrogen, Ci-ealkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, Ci-eaminoalkyl, Ci-eheteroalkyl, C2-6alkenyl, C2-6alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -LX4-heterocycloalkyl, -LX4-cycloalkyl, -LX4- aryl, or -LX4-heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more RX4a;RX4’ is hydrogen or Ci-ealkyl, wherein the alkyl is optionally substituted with one or more RX4a; orRn4and RX4’ are taken together with the intervening atoms to form a 5- to 6- membered heterocycloalkyl, which is optionally substituted with one or more RX4a;LX4is Ci-6alkylene or Ci-eheteroalkylene, -O-, -S-, or -NRa-, wherein the alkylene and heteroalkylene is optionally substituted with one or more RX4a; each RX4ais independently halogen, C1-6 alkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, C1- Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, - SF5, -S(=O)2NRcRd, -S(=O)(=NRa)Ra, -N=S(=O)RcRd, -NRaS(=O)2Ra, amidinyl, -NRaC(=NH)(NRa)2, - NRaS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =0, =S, or =N(Ra), wherein each of the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, alkenyl, and alkynyl is optionally substituted with one or more Re;*X3 represents the point of attachment to X3; and*X5 represents the point of attachment to X5.

44. The peptide of any one of claims 26 to 43, or a pharmaceutically acceptable salt thereof, whereinwherein:Rn4is hydrogen or C1-3 alkyl, wherein the alkyl is optionally substituted with one or more RX4a;RX4is hydrogen, Ci-ealkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, Ci-eaminoalkyl, Ci-eheteroalkyl, -LX4-5-6 membered heterocycloalkyl, -LX4-C3-6cycloalkyl, -LX4-C6-ioaryl, or -LX4-5-10 membered heteroaryl, wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more RX4a;LX4is Ci-6alkylene or Ci-sheteroalkylene, wherein the alkylene and heteroalkylene is optionally substituted with one or more RX4a; each RX4ais independently halogen, Ci-ealkyl, Ci-Cehaloalkyl, C-i-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci- Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, - SF5, -S(=O)2NRcRd, -S(=O)(=NRa)Ra, -N=S(=O)RcRd, -NRaS(=O)2Ra, amidinyl, -NRaC(=NH)(NRa)2, - NRaS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =0, =S, or =N(Ra), wherein each of the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, alkenyl, and alkynyl is optionally substituted with one or more Re;*X3 represents the point of attachment to X3; and*X5 represents the point of attachment to X5.

45. The peptide of claim 43 or 44, or a pharmaceutically acceptable salt thereof, whereinRX4is Ci-ealkyl, Ci-eheteroalkyl, -LX4-piperidinyl, LX4-piperazinyl, -LX4-phenyl, or -LX4-pyridinyl, wherein each of the alkyl, heteroalkyl, phenyl, pyridinyl, piperidinyl, and piperazinyl is optionally substituted with one or more RX4a.

46. The peptide of any one of claims 43 to 45, or a pharmaceutically acceptable salt thereof, wherein each RX4ais independently halogen, Ci-ealkyl, Ci-Cehaloalkyl, C-i-Cehydroxyalkyl, Ci-Ceaminoalkyl, C1- C6heteroalkyl, -CN, -N02, -0Ra, -SRa, -NRcRd, -S(=0)Ra, -S(=0)2Ra, -S(=0)2NRcRd, -NRaS(=0)2Ra, -NRaC(=NH)(NRa)2, -C(=0)Ra, -C(=0)0Ra, -0C(=0)Ra, -0C(=0)0Ra, -0C(=0)NRcRd, - NRaC(=0)Ra, -NRaC(=0)0Ra, -NRaC(=0)NRcRd, -C(=0)NRcRd, or =0, wherein each of the alkyl and heteroalkyl is optionally substituted with one or more Re.

47. The peptide of any one of claims 26 to 46, or a pharmaceutically acceptable salt thereof, wherein Rn5is hydrogen or methyl; ring A5 is a Ce- aryl, 5-10 membered heteroaryl, Ce-iocycloalkyl, or 5-10 membered heterocycloalkyl; each RX5is independently Ci-ealkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, Ci-eaminoalkyl, Ci-eheteroalkyl, C2- ealkenyl, C2-6alkynyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Ra, -S(=O)2Ra, - S(=O)2NRcRd, -S(=O)(=NRa)Ra, -N=S(=O)NRcRd, -NRaS(=O)2Ra, amidinyl, -NRaC(=NH)NRcRd, - NRaS(=O)2NRcRd, -C(=0)Ra, -C(=0)0Ra, -0C(=0)Ra, -0C(=0)0Ra, -0C(=0)NRcRd, -NRaC(=0)Ra, -NRaC(=0)0Ra, -NRaC(=0)NRcRd, -C(=0)NRcRd, -P(=0)(0Rc)(0Rd), -P(=0)RcRd, Ce- aryl, 5-10 membered heteroaryl, Cs-ecycloalkyl, 5-6 membered heterocycloalkyl, -LX5-5-6 memberedheterocycloalkyl, -LX5-C3-6cycloalkyl, -LX5-C6-ioaryl, or -LX5-5-10 membered heteroaryl, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more RX5a; or two RX5are taken together to form =0; andLX5is Ci-6alkylene or Ci-eheteroalkylene, wherein the alkylene and heteroalkylene is optionally substituted with one or more RX5a.

48. The peptide of any one of claims 26 to 47, or a pharmaceutically acceptable salt thereof, wherein ring A5 is a phenyl, naphthyl, pyridinyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, or tetrahydropyranyl; each RX5is independently halogen, Ci-ealkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, Ci-eaminoalkyl, Ci- sheteroalkyl, -CN, -N02, -0Ra, -SRa, -NRcRd, -S(=0)Ra, -S(=0)2Ra, -S(=0)2NRcRd, -NRaS(=0)2Ra, - NRaC(=NH)NRcRd, -NRaS(=0)2NRcRd, -C(=0)Ra, -C(=0)0Ra, -0C(=0)Ra, -0C(=0)0Ra, - 0C(=0)NRcRd, -NRaC(=0)Ra, -NRaC(=0)0Ra, -NRaC(=0)NRcRd, -C(=0)NRcRd, -LX5-piperidinyl, or LX5-piperazinyl, wherein each of the alkyl, heteroalkyl, piperidinyl, and piperazinyl are optionally substituted with one or more RX5a; or two RX5are taken together to form =0; kx5 is 1 or 2; and mx5 Is O, 1 , or 2.

49. The peptide of any one of claims 26 to 48, or a pharmaceutically acceptable salt thereof, wherein each RX5ais independently halogen, Ci-ealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci- C6heteroalkyl, -CN, -N02, -0Ra, -SRa, -NRcRd, -S(=0)Ra, -S(=0)2Ra, -S(=0)2NRcRd, -NRaS(=0)2Ra, -NRaC(=NH)(NRa)2, -C(=0)Ra, -C(=0)0Ra, -0C(=0)Ra, -0C(=0)0Ra, -0C(=0)NRcRd, - NRaC(=0)Ra, -NRaC(=0)0Ra, -NRaC(=0)NRcRd, -C(=0)NRcRd, or =0, wherein each of the alkyl and heteroalkyl is optionally substituted with one or more Re.

50. The peptide of any one of claims 26 to 49, or a pharmaceutically acceptable salt thereof, whereinRn6is hydrogen or methyl;RX6is Ci-ealkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, Ci-eaminoalkyl, Ci-eheteroalkyl, C2-ealkenyl, C2-6alkynyl, Ce- aryl, 5-10 membered heteroaryl, Cs-ecycloalkyl, 5-6 membered heterocycloalkyl, -LX6-5-6 membered heterocycloalkyl, -LX6-C3-6cycloalkyl, -LX6-C6-ioaryl, or -LX6-5-10 membered heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more RX6a; andLX6is Ci-6alkylene or Ci-cheteroalkylene, wherein the alkylene and heteroalkylene is optionally substituted with one or more RX6a.51 . The peptide of any one of claims 26 to 50, or a pharmaceutically acceptable salt thereof, whereinRX6is Ci-ealkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, Ci-eaminoalkyl, Ci-eheteroalkyl, Cs ecycloalkyl, 5-6 membered heterocycloalkyl, -LX6-5-6 membered heterocycloalkyl, -LX6- Cs ecycloalkyl, -LX6-phenyl or -LX6-6 membered heteroaryl, wherein each of the alkyl, heteroalkyl, phenyl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more RX6a.

52. The peptide of any one of claims 26 to 51 , or a pharmaceutically acceptable salt thereof, wherein each RX6ais independently halogen, C1-6 alkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci- C6heteroalkyl, -CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRaS(=O)2Ra, -NRaC(=NH)(NRa)2, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)NRcRd, - NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, or =0, wherein each of the alkyl and heteroalkyl is optionally substituted with one or more Re.

53. The peptide of any one of claims 26 to 52, or a pharmaceutically acceptable salt thereof, whereinRn7is hydrogen or methyl; andRX7is Ci-ealkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, Ci-eaminoalkyl, Ci-eheteroalkyl, C2-ealkenyl, C2-ealkynyl, Cs-ecycloalkyl, or 5-6 membered heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more RX7a.

54. The peptide of any one of claims 26 to 53, or a pharmaceutically acceptable salt thereof, whereinRX7is Ci-ealkyl, Ci-eheteroalkyl, Cs-ecycloalkyl, or 5-6 membered heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more RX7a.

55. The peptide of any one of claims 26 to 54, or a pharmaceutically acceptable salt thereof, wherein each RX7ais independently halogen, -CN, -ORa, -SRa, -NRcRd, -C(=0)Ra, -C(=0)0Ra, -0C(=0)Ra, -0C(=0)0Ra, -0C(=0)NRcRd, -NRaC(=0)Ra, -NRaC(=0)0Ra, -NRaC(=0)NRcRd, -C(=0)NRcRd, or =0.

56. The peptide of any one of claims 26 to 55, or a pharmaceutically acceptable salt thereof, wherein ring A8 is a Ce- aryl or 5-10 membered heteroaryl; each RX8is independently Ci-ealkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, Ci-eaminoalkyl, Ci-eheteroalkyl, C2- ealkenyl, C2-ealkynyl, halogen, -CN, -NO2, -ORa, -SRa, -SFs, -NRcRd, -S(=O)Ra, -S(=O)2Ra, - S(=0)2RcRd, -S(=O)(=NRa)Ra, -N=S(=O) RcRd, -NRaS(=O)2Ra, amidinyl, -NRaC(=NH)NRcRd, - NRaS(=0)2RcRd, -C(=0)Ra, -C(=0)0Ra, -0C(=0)Ra, -0C(=0)0Ra, -0C(=0)NRcRd, -NRaC(=0)Ra, - NRaC(=0)0Ra, -NRaC(=0)NRcRd, -C(=0)NRcRd, -P(=0)(0Rc)(0Rd), -P(=0)RcRd, C6-ioaryl, 5-10 membered heteroaryl, Cs-ecycloalkyl, 5-6 membered heterocycloalkyl, -LX8-5-6 membered heterocycloalkyl, -LX8- Ce-ecycloalkyl, -LX8- Ce-waryl, or -LX8-5-10 membered heteroaryl, whereineach of the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more RX8a; or two RX8are taken together to form =0; andLX8is Ci-6alkylene or Ci-6heteroalkylene, wherein the alkylene and heteroalkylene is optionally substituted with one or more RX8a.

57. The peptide of any one of claims 26 to 56, or a pharmaceutically acceptable salt thereof, wherein ring A8 is a phenyl, pyridinyl, indolyl, azaindolyl, indazolyl, or benzimidazolyl; each RX8is independently halogen, Ci-ealkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, Ci-eaminoalkyl, Ci- sheteroalkyl, -CN, -N02, -0Ra, -SRa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRaS(=O)2Ra, - NRaC(=NH)NRcRd, -NRaS(=O)2NRcRd, -C(=0)Ra, -C(=0)0Ra, -0C(=0)Ra, -0C(=0)0Ra, - 0C(=0)NRcRd, -NRaC(=0)Ra, -NRaC(=0)0Ra, -NRaC(=0)NRcRd, -C(=0)NRcRd, -LX8-piperidinyl, or LX8-piperazinyl, wherein each of the alkyl, heteroalkyl, piperidinyl, and piperazinyl are optionally substituted with one or more RX8a; or two RX5are taken together to form =0; kx8 is 1 or 2; and mx8 Is O, 1 , or 2.

58. The peptide of any one of claims 26 to 57, or a pharmaceutically acceptable salt thereof, wherein each RX8ais independently halogen, C1-6 alkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci- C6heteroalkyl, -CN, -N02, -0Ra, -SRa, -NRcRd, -S(=0)Ra, -S(=0)2Ra, -S(=0)2NRcRd, -NRaS(=0)2Ra, -NRaC(=NH)(NRa)2, -C(=0)Ra, -C(=0)0Ra, -0C(=0)Ra, -0C(=0)0Ra, -0C(=0)NRcRd, - NRaC(=0)Ra, -NRaC(=0)0Ra, -NRaC(=0)NRcRd, -C(=0)NRcRd, or =0, wherein each of the alkyl and heteroalkyl is optionally substituted with one or more Re.

59. The peptide of any one of claims 26 to 58, or a pharmaceutically acceptable salt thereof, wherein Rn9is hydrogen or methyl; ring A9 is a Ce- aryl or 5-10 membered heteroaryl; and each RX9is independently halogen, Ci-ealkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, Ci-eaminoalkyl, Ci- eheteroalkyl, C2-ealkenyl, C2-6alkynyl, -CN, -N02, -0Ra, -SRa, -SFs, or -NRcRd, wherein each of the alkyl, heteroalkyl, alkenyl, and alkynyl is optionally substituted with one or more RX9a; or two RX9are taken together to form =0.

60. The peptide of any one of claims 26 to 59, or a pharmaceutically acceptable salt thereof, wherein ring A9 is a phenyl, naphthyl, pyridinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, or isoquinolinyl;each RX9is independently halogen, Ci-ealkyl, Ci-ehaloalkyl, -CN, -ORa, -SRa, or -NRcRd, wherein each of the alkyl and heteroalkyl is optionally substituted with one or more RX9a; kx9 is 1 or 2; and mx9 Is O, 1 , or 2.61 . The peptide of any one of claims 26 to 60, or a pharmaceutically acceptable salt thereof, wherein each RX9ais independently halogen, Ci-ealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci- C6heteroalkyl, -CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRaS(=O)2Ra, -NRaC(=NH)(NRa)2, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)NRcRd, - NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, or =0, wherein each of the alkyl and heteroalkyl is optionally substituted with one or more Re.

62. The peptide of any one of claims 26 to 61 , or a pharmaceutically acceptable salt thereof, wherein ring A11 is a Ce- aryl or 5-10 membered heteroaryl; each RX11is independently Ci-ealkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, Ci-eaminoalkyl, Ci-eheteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2RcRd, -S(=O)(=NRa)Ra, -N=S(=O)RcRd, -NRaS(=O)2Ra, amidinyl, -NRaC(=NH)NRcRd, -NRaS(=O)2RcRd, -C(=0)Ra, - C(=0)0Ra, -0C(=0)Ra, -0C(=0)0Ra, -OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, - NRaC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-ioaryl, 5-10 membered heteroaryl, Cs-ecycloalkyl, 5-6 membered heterocycloalkyl, -Lx11-5-6 membered heterocycloalkyl, - LX11- C3-6cycloalkyl, -LX11- Ce-waryl, or -Lx11-5-10 membered heteroaryl, wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more Rx11a; or two RX11are taken together to form =0; andLX11is Ciwalkylene, Ci-eheteroalkylene, or -O-, wherein the alkylene and heteroalkylene is optionally substituted with one or more Rx11a.

63. The peptide of any one of claims 26 to 62, or a pharmaceutically acceptable salt thereof, wherein ring A11 is a phenyl or pyridinyl; each RX11is independently Ci-ealkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, Ci-eaminoalkyl, Ci-eheteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2RcRd, -NRaS(=O)2Ra, - NRaC(=NH)NRcRd, -NRaS(=O)2RcRd, -C(=0)Ra, -C(=0)0Ra, -0C(=0)Ra, -0C(=0)0Ra, - OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, C6-ioaryl, 5-10 membered heteroaryl, Cs-ecycloalkyl, 5-6 membered heterocycloalkyl, -Lx11-5-6 membered heterocycloalkyl, -LX11- Ce-ecycloalkyl, -LX11- Ce- aryl, or -Lx11-5-10 membered heteroaryl, whereineach of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more Rx11a; or two RX11are taken together to form =0; kx11 is 1 , 2, 3, or 4; and mx11 Is O, 1 , or 2.

64. The peptide of any one of claims 26 to 63, or a pharmaceutically acceptable salt thereof, wherein each RX11is independently phenyl, pyridinyl, pyrrolyl, pyrazolyl, imidazolyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, -Lx11-5-6 membered heterocycloalkyl, - -Lx11-phenyl, or -Lx11-pyridinyl, wherein each of the phenyl, pyridinyl, pyrrolyl, pyrazolyl, imidazolyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, and heterocycloalkyl is optionally substituted with one or more Rx11a.

65. The peptide of any one of claims 26 to 64, or a pharmaceutically acceptable salt thereof, wherein each Rx11ais independently halogen, Ci-ealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-C6heteroalkyl, -CN, -N02, -0Ra, -SRa, -NRcRd, -S(=0)Ra, -S(=0)2Ra, -S(=0)2NRcRd, -NRaS(=0)2Ra, -NRaC(=NH)(NRa)2, -C(=0)Ra, -C(=0)0Ra, -0C(=0)Ra, -0C(=0)0Ra, -0C(=0)NRcRd, - NRaC(=0)Ra, -NRaC(=0)0Ra, -NRaC(=0)NRcRd, -C(=0)NRcRd, or =0, wherein each of the alkyl and heteroalkyl is optionally substituted with one or more Re.

66. The peptide of any one of claims 1-65, wherein the peptide or the pharmaceutically acceptable salt thereof has a cyclic structure.

67. The peptide of any one of claims 1-66, wherein the peptide or the pharmaceutically acceptable salt thereof has a cyclic structure, wherein the first amino acid (or X1) is covalently linked to the last amino acid (or X12).

68. The peptide of any one of claims 1-67, wherein the peptide or the pharmaceutically acceptable salt thereof has a cyclic structure having an amino acid in the first residue X1 and a N-methylated cysteine residue, and wherein the amino acid in X1 and the N-methylated cysteine residue or variant thereof form a covalent bond.

69. The peptide of any one of claims 1-68, or a pharmaceutically acceptable salt thereof, wherein the peptide has a monocyclic structure.

70. The peptide of claim 69, or a pharmaceutically acceptable salt thereof, wherein the monocyclic structure is formed by a covalent bond between the amino acid X1 and a cysteine or a variant thereof.71 . The peptide of any one of claims 1 -70, or a pharmaceutically acceptable salt thereof, wherein the peptide has a structure of Formula (1-1),Formula (1-1), wherein,R1is selected from the group consisting of -NH2 and -OH;R2is C1-3 alkyl;R3is C1-3 alkylene, optionally substituted with one or more R4, wherein; each R4is independently C1-3 alkyl or C3-6 cycloalkyl,; kxR is 1, 2, 3, 4, 5, or 6;XR is selected from the group consisting of S, C or 0; and wherein X1 to X11 have the definitions described in Formula (I).

72. The peptide of any one of claims 1-71, wherein the peptide or the pharmaceutically acceptable salt thereof comprises a sequence with up to 1, 2, 3, 4, or 5 substitutions by a conserved variant compared to any one of the sequences selected from SEQ ID NOs: 1-72.

73. The peptide of any one of claims 1-72, wherein the peptide or the pharmaceutically acceptable salt thereof consists of an amino acid sequence selected from SEQ ID NOs: 1-72.

74. The peptide of any one of claims 1-73, or a pharmaceutically acceptable salt thereof, wherein the peptide has a binding affinity to a human GPC3 of at most 100 nM as determined by Kd in surface plasmon resonance (SPR) analysis.

75. A peptide of any one of claims 1-74, or a pharmaceutically acceptable salt thereof, covalently linked to a linker that is capable of connecting the peptide to a payload molecule.

76. The peptide of claim 75, or a pharmaceutically acceptable salt thereof, wherein the linker is attached to a lysine of the peptide.

77. The peptide of claim 75 or 76, or a pharmaceutically acceptable salt thereof, wherein the linker is attached to the peptide via the N terminus of the peptide.

78. The peptide of claim 75 or 76, or a pharmaceutically acceptable salt thereof, wherein the linker is attached to the peptide via the C terminus of the peptide.

79. The peptide of claim 75 or 76, or a pharmaceutically acceptable salt thereof, wherein the linker is attached to the peptide via a non-terminal amino acid residue of the peptide.

80. The peptide of claim 75 or 76, or a pharmaceutically acceptable salt thereof, wherein the linker isattached to the 1st amino acid residue (or X1), the 2nd amino acid residue (or X2), the 3rd amino acid residue (or X3), the 4th amino acid residue (or X4), the 8th amino acid residue (or X8), or the 12th amino acid residue (or X12).81 . The peptide of claim 80, or a pharmaceutically acceptable salt thereof, wherein the linker is attached to the 1 st amino acid residue or X1 .

82. The peptide of claim 80, or a pharmaceutically acceptable salt thereof, wherein the linker is attached to the last amino acid residue, or X12.

83. The peptide of claim 80, or a pharmaceutically acceptable salt thereof, wherein the linker is attached to the 2ndamino acid residue (or X2).

84. The peptide of claim 80, or a pharmaceutically acceptable salt thereof, wherein the linker is attached to the 3rdamino acid residue (or X3).

85. The peptide of claim 80, or a pharmaceutically acceptable salt thereof, wherein the linker is attached to the 4thamino acid residue (or X4).

86. The peptide of claim 80, or a pharmaceutically acceptable salt thereof, wherein the linker is attached to the 8thamino acid residue (or X8).

87. The peptide of any one of claims 75 to 86, or a pharmaceutically acceptable salt thereof, wherein the linker is a bond.

88. The peptide of any one of claims 75 to 86, or a pharmaceutically acceptable salt thereof, wherein the linker comprises 3 to 30 intervening non-hydrdogen, organic atoms between the payload molecule and the peptide.

89. The peptide of any one of claims 75 to 86, or a pharmaceutically acceptable salt thereof, wherein the linker comprises 6 to 18 intervening non-hydrogen, organic atoms between the payload molecule and the peptide.

90. The peptide of claims 88 or 89, or a pharmaceutically acceptable salt thereof, wherein the intervening atoms comprise 1 to 6 nitrogen atoms and 0 to 4 oxygen atoms.91 . The peptide of any one of claims 75 to 86 or 88 to 90, or a pharmaceutically acceptable salt thereof, wherein the linker comprises one or more amino acid residues.

92. The peptide of claim 91, pharmaceutically acceptable salt thereof, wherein the linker comprises one amino acid residue.

93. The peptide of claim 91, or a pharmaceutically acceptable salt thereof, wherein the linker comprises at least two contiguous amnio acid residues.

94. The peptide of any one of claims 91 to 93, wherein the one or more amino acid residues are selectedfrom a lysine residue, an alanine residue, a glycine residue, a D-phenylalanine residue, a histidine residue, a dAtb residue, or a D-glutamate residue.

95. The peptide of any one of claims 75 to 86, wherein the linker comprises one or more structures selected from AEEA, AEEP, AEEEP, and AEEEEP.

96. The peptide of any one of claims 75 to 86, wherein the linker has a structure of Formula (11-1)Formula (11-1) wherein each L is independently -O-, -NRL-, -N(RL)2-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, - NRLC(=O)NRL-, -NRLC(=S)NRL-, -CRL=N-, -N=CRL, -NRLS(=O)2-, -S(=O)2NRL-, -C(=O)NRLS(=O)2-, - S(=O)2NRLC(=O)-, substituted or unsubstituted C3-15 cycloalkyl, substituted or unsubstituted Ci-i2heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-30 alkylene, substituted or unsubstituted C2-3o alkenylene, substituted or unsubstituted C2-3o alkynylene, substituted or unsubstituted C1-30 heteroalkylene, -(C1-30 alkylene)-O-, -0-(Ci-3o alkylene)-, -(C1-30 alkylene)-NRL- , -NRL-(CI-3O alkylene)-, -(C1-30 alkylene)-N(RL)2-, or -N(RL)2-(CI-3O alkylene)-; and each RLis independently hydrogen, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C1-4 heteroalkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-s alkynyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C2-? heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and n is 1 to 20.

97. The peptide of claim 96, wherein the linker comprises a structure of Formula (11-1 a), L1-L2-L3Formula (11-1 a) wherein each of L1and L3is independently -O-, -NRL-, -N(RL)2-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, -CH=CH-, =CH-, -C C-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, - OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -NRLS(=O)2-, -S(=O)2NRL-, -C(=O)NRLS(=O)2-, or - S(=O)2NRLC(=O)-; andL2is absent, substituted or unsubstituted C1-30 alkylene, or substituted or unsubstituted C1-30 heteroalkylene.

98. The peptide of claim 97, wherein L1is -NH-.

99. The peptide of claim 97 or 98, wherein L2is substituted or unsubstituted C1-30 alkylene, or substituted orunsubstituted C1-30 heteroalkylene.

100. The peptide of claim 97 or 98, wherein L2is substituted or unsubstituted C1-18 alkylene, or substituted or unsubstituted C1-18 heteroalkylene.

101. The peptide of any one of claims 97 to 100, wherein L2is optionally substituted with one or more substituents selected from -OH, -SH, oxo, amino, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 aminoalkyl, -C(=O)ORL, -OC(=O)RL, -OC(=O)ORL, -C(=O)N(RL)2, -NRLC(=O)RL, -OC(=O)N(RL)2, and - NRLC(=O)ORL; and the C1-6 alkyl is further optionally substituted with one or more substituents chosen from -OH, -SH, oxo, amino, CB-IO aryl, 6- to 10- membered heteroaryl, -C(=O)ORL, -OC(=O)RL, - OC(=O)ORL, -C(=O)N(RL)2, -NRLC(=O)RL, -OC(=O)N(RL)2, and -NRLC(=O)ORL.

102. The peptide of any one of claims 97 to 101 , wherein L3is -NH-.

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

104. A conjugate comprising the peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 to 102, and a substance or a payload molecule, wherein the substance or payload molecule is selected from the group consisting of: a nucleotide, a small molecule, a medium sized molecule (e.g., with a M.W. of about 1 ,000-2,500 Da), a large sized molecule (e.g., with a M.W. of >2,500 Da), a polymer compound, a protein, a peptide, a tag, a biological fragment, a carrier including pharmaceutical compound, or a combination thereof.

105. A method of treating a disease or disorder characterized by overexpression of GPC3, in a subject in need of treatment, the method comprising administering to the subject the peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 to 102, the conjugate of claim 104, or the pharmaceutical composition of claim 103.

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

107. The method of claim 106, wherein the cancer is a solid tumor or hematological cancer.

108. A kit, tester, or composition for determining the expression level of GPC3 in a sample, wherein the kit, tester, or composition comprises the peptide or a salt thereof according to any one of claims 1 to 102, the conjugate of claim 104, or the pharmaceutical composition of claim 103.

109. The kit, tester, or composition of claim 108, adapted for use in a method of diagnosing disease or disorder characterized by an overexpression or a decreased expression of GPC3.

110. The kit, tester, or composition of claim 108 or 109, wherein the sample is from a subject having a disease or disorder characterized by an overexpression or a decreased expression of GPC3.

111. Use of the peptide or pharmaceutically acceptable salt thereof according to any one of the preceding claims in the manufacture of a medicament for diagnosing and / or treating a disease or disordercharacterized by an overexpression or a decreased expression of GPC3.

112. The peptide or pharmaceutically acceptable salt thereof according to any one of the preceding claims, for use in diagnosing and / or treating a disease or disorder characterized by an overexpression or a decreased expression of GPC3.