Peptidomimetic macrocycles

1. A peptidomimetic macrocycle comprising an amino acid sequence which is at least 60% identical to an amino acid sequence of SEQ ID NO. 689.

2. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle comprises an amino acid sequence which is at least 80% identical to an amino acid sequence of SEQ ID NO. 689.

3. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle comprises an amino acid sequence which is at least 90% identical to an amino acid sequence of SEQ ID NO. 689.

4. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle comprises an amino acid sequence which is at least 95% identical to an amino acid sequence of SEQ ID NO. 689.

5. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle comprises an amino acid sequence which is SEQ ID NO. 689.

6. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle comprises a helix.

7. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle comprises an α-helix.

8. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle comprises an α,α-disubstituted amino acid.

9. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle comprises a crosslinker linking the α-positions of at least two amino acids.

10. The peptidomimetic macrocycle of claim 9 , wherein at least one of said two amino acids is an α,α-disubstituted amino acid.

11. The peptidomimetic macrocycle of any one of claims 1 - 10 , wherein the peptidomimetic macrocycle has the formula:

wherein:

each A, C, D, and E is independently a natural or non-natural amino acid, and D and E independently optionally include a capping group;

B is a natural or non-natural amino acid, amino acid analog,

 [—NH-L 3 -CO—], [—NH-L 3 -SO 2 —], or [—NH-L 3 -];

R 1 and R 2 are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-;

R 3 is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ;

L is a macrocycle-forming linker of the formula -L 1 -L 2 -;

L 1 and L 2 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R 4 —K—R 4 —] n , each being optionally substituted with R 5 ;

each R 4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;

each K is O, S, SO, SO 2 , CO, CO 2 , or CONR 3 ;

each R 5 is independently halogen, alkyl, —OR 6 , —N(R 6 ) 2 , —SR 6 , —SOR 6 , —SO 2 R 6 , —CO 2 R 6 , a fluorescent moiety, a radioisotope or a therapeutic agent;

each R 6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;

R 7 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with a D residue;

R 8 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue;

v and w are independently integers from 1-1000;

u is an integer from 1-10;

x, y and z are independently integers from 0-10; and

n is an integer from 1-5.

12. The peptidomimetic macrocycle of claim 11 , wherein L does not include a thioether or a triazole.

13. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle comprises a cross linker linking a backbone amino group of a first amino acid to a second amino acid within the peptidomimetic macrocycle.

14. The peptidomimetic macrocycle of claim 13 , wherein the peptidomimetic macrocycle has the formula (IV) or (IVa):

wherein:

each A, C, D, and E is independently a natural or non-natural amino acid, and D and E independently optionally include a capping group;

B is a natural or non-natural amino acid, amino acid analog,

 [—NH-L 3 -CO—], [—NH-L 3 -SO 2 ], or [—NH-L 3 ];

R 1 and R 2 are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-, or part of a cyclic structure with an E residue;

R 3 is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ;

L 1 and L 2 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R 4 —K—R 4 —] n , each being optionally substituted with R 5 ;

each R 4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;

each K is O, S, SO, SO 2 , CO, CO 2 , or CONR 3 ;

each R 5 is independently halogen, alkyl, —OR 6 , —N(R 6 ) 2 , —SR 6 , —SOR 6 , —SO 2 R 6 , —CO 2 R 6 , a fluorescent moiety, a radioisotope or a therapeutic agent;

each R 6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;

R 7 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ;

v and ware independently integers from 1-1000;

u is an integer from 1-10;

x, y and z are independently integers from 0-10; and

n is an integer from 1-5.

15. The peptidomimetic macrocycle of claim 14 , wherein L 1 and L 2 either alone or in combination do not include a thioether or a triazole.

16. The peptidomimetic macrocycle of claim 11 , wherein L 1 and L 2 are independently alkylene, alkenylene or alkynylene.

17. The peptidomimetic macrocycle of claim 11 , wherein L 1 and L 2 are independently C 3 -C 10 alkylene or alkenylene.

18. The peptidomimetic macrocycle of claim 17 , wherein L 1 and L 2 are independently C 3 -C 6 alkylene or alkenylene.

19. The peptidomimetic macrocycle of claim 11 , wherein R 1 and R 2 are H.

20. The peptidomimetic macrocycle of claim 11 , wherein R 1 and R 2 are independently alkyl.

21. The peptidomimetic macrocycle of claim 11 , wherein R 1 and R 2 are methyl.

22. A method of treating cancer in a subject comprising administering to the subject a peptidomimetic macrocycle of any one of claims 1 - 10 .

23. A method of modulating the activity of a p53 protein, a HDM2 protein, a HDMX protein, or a combination thereof, in a subject comprising administering to the subject a peptidomimetic macrocycle of any one of claims 1 - 10 .

24. A method of antagonizing the interaction between a p53 protein and a HDM2 proteins, between a p53 protein and a HDMX protein, or a combination thereof, in a subject comprising administering to the subject a peptidomimetic macrocycle of any one of claims 1 - 10 .