Cyclic peptide binder against oncogenic K-Ras

1. A cyclic peptide represented by Formula I:

wherein:

Z1 and Z2 are each non-naturally occurring amino acids;

V1-V2-V3-V4-V5 is a five amino acid variable region, wherein V1 is L or V, V2 is R, homoR, or guanidinoF, V3 is G, V4 is D, P, E, A, N, or Q, and V5 is guanidinoF or R;

L is a linker moiety; and

B m is an optional group, wherein m is 0 or 1.

2. The cyclic peptide of claim 1 , wherein Z1 and Z2 are not the same.

3. The cyclic peptide of claim 1 , wherein when Z1 is Pra, Z2 is OrnN3 or Az4, when Z1 is OrnN3 or Az4, Z2 is Pra.

4. The cyclic peptide of claim 1 , wherein Z1 is Pra and Z2 is Az4.

5. The cyclic peptide of claim 1 , wherein Z1 is Pra and Z2 is OrnN3.

6. The cyclic peptide of claim 1 , wherein Z1 is Az4 and Z2 is Pra.

7. The cyclic peptide of claim 1 , wherein V1-V2-V3-V4-V5 have a sequence selected from the group consisting of SEQ ID NOs:10-20.

8. The cyclic peptide of claim 1 , wherein V1-V2-V3-V4-V5 is SEQ ID NO: 7, 11, or 16.

9. The cyclic peptide of claim 8 , wherein V1-V2-V3-V4-V5 is SEQ ID NO:16.

10. The cyclic peptide of claim 1 , wherein L is a triazole group.

11. The cyclic peptide of claim 1 , wherein L is 1,4-triazole.

12. The cyclic peptide of claim 1 , wherein Z1 is Pra and Z2 is Az4, and wherein V1-V2-V3-V4-V5 is SEQ ID NO:16.

13. The cyclic peptide of claim 1 , wherein Z1 is Pra and Z2 is Az4, and wherein L is 1,4-triazole.

14. The cyclic peptide of claim 1 , wherein Z1 is Pra and Z2 is Az4, wherein m is 1, wherein B is a combination of a spacer group and a detection tag.

15. The cyclic peptide of claim 1 , wherein Z1 is Pra and Z2 is Az4, wherein m is 1, wherein B is a combination of a spacer group and a detection tag, and wherein the spacer group is PEG and the detection tag is biotin.

16. The cyclic peptide of claim 1 , wherein V1-V2-V3-V4-V5 is SEQ ID NO:16, and wherein L is 1,4-triazole.

17. The cyclic peptide of claim 1 , wherein V1-V2-V3-V4-V5 is SEQ ID NO:16, wherein m is 1, and wherein B is a combination of a spacer group and a detection tag.

18. The cyclic peptide of claim 1 , wherein V1-V2-V3-V4-V5 is SEQ ID NO:16, wherein m is 1, wherein B is a combination of a spacer group and a detection tag, and wherein the spacer group is PEG and the detection tag is biotin.

19. The cyclic peptide of claim 1 , wherein Z1 is Pra and Z2 is Az4, wherein V1-V2-V3-V4-V5 is SEQ ID NO:16, and wherein L is 1,4-triazole.

20. The cyclic peptide of claim 1 , wherein Z1 is Pra and Z2 is Az4, wherein V1-V2-V3-V4-V5 is SEQ ID NO:16, wherein m is 1, and wherein B is a combination of a spacer group and a detection tag.

21. The cyclic peptide of claim 1 , wherein Z1 is Pra and Z2 is Az4, wherein V1-V2-V3-V4-V5 is SEQ ID NO:16, wherein m is 1, wherein B is a combination of a spacer group and a detection tag, and wherein the spacer group is PEG and the detection tag is biotin.

22. The cyclic peptide of claim 1 , wherein Z1 is Pra and Z2 is Az4, wherein V1-V2-V3-V4-V5 is SEQ ID NO:16, wherein L is 1,4-triazole, wherein m is 1, and wherein B is a combination of a spacer group and a detection tag.

23. The cyclic peptide of claim 1 , wherein Z1 is Pra and Z2 is Az4, wherein V1-V2-V3-V4-V5 is SEQ ID NO:16, wherein L is 1,4-triazole, wherein m is 1, wherein B is a combination of a spacer group and a detection tag, and wherein the spacer group is PEG and the detection tag is biotin.

24. The cyclic peptide of claim 1 having the structure:

25. The cyclic peptide of claim 1 , wherein B is conjugated to any group of the cyclic peptide.

26. The cyclic peptide of claim 25 , wherein B is conjugated to the C-terminus of Z2.

27. The cyclic peptide of claim 1 , wherein when m is 1, and wherein B is a spacer group, a detection tag, or a combination of a spacer group and a detection tag.

28. The cyclic peptide of claim 27 , wherein B is a spacer group.

29. The cyclic peptide of claim 27 , wherein the detection tag is a chemical moiety that can be selectively bound.

30. The cyclic peptide of claim 27 , wherein the detection tag is an affinity tag, a fluorescent tag, or a fluorescently labeled affinity tag.

31. The cyclic peptide of claim 27 , wherein the detection tag is an affinity tag selected from the group consisting of biotin, streptavidin, poly-histidine, poly-arginine, FLAG, cyclodextrin, adamantane, and combinations thereof.

32. The cyclic peptide of claim 27 , wherein the spacer group is polyethylene glycol (PEG) or 6-aminohexanoic acid (Ahx).

33. The cyclic peptide of claim 32 , wherein the spacer group includes 2 to 24 PEG units.

34. The cyclic peptide of claim 32 , wherein the spacer group includes 2 to 15 PEG units.

35. The cyclic peptide of claim 32 , wherein the spacer group includes 2 to 10 PEG units.

36. The cyclic peptide of claim 32 , wherein the spacer group includes 2 to 5 PEG units.

37. The cyclic peptide of claim 32 , wherein the spacer group includes 2 to 4 PEG units.

38. The cyclic peptide of claim 32 , wherein the spacer group includes 2 to 3 PEG units.

39. The cyclic peptide of claim 27 , wherein B is a combination of a spacer group and a detection tag.

40. The cyclic peptide of claim 37 , wherein the spacer group is PEG and the detection tag is biotin.

41. A cyclic peptide comprising the structure:

42. The cyclic peptide of claim 1 , wherein the cyclic peptide is conjugated with a moiety.

43. A method of inhibiting K-Ras G12D oncoprotein in a cancer cell expressing K-Ras G12D, the method comprising:

incubating the cancer cell with the cyclic peptide of claim 1 .

44. The method of claim 43 , wherein the cancer cell is pancreatic, colorectal, lung, biliary tract, or ovarian cancer.

45. A method of inhibiting K-Ras G12D oncoprotein in a cancer cell expressing K-Ras G12D, the method comprising:

incubating the cancer cell with the cyclic peptide of claim 42 .

46. The method of claim 45 , wherein the cancer cell is pancreatic, colorectal, lung, biliary tract, or ovarian cancer.