The present invention provides novel peptidomimetic macrocycles and methods of using such macrocycles for the treatment of disease.
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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 amin
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-L3-CO—], [—NH-L3-SO2—], or [—NH-L3-];R1 and R2 are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-;R3 is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5;L is a macrocycle-forming linker of the formula -L1-L2-;L1 and L2 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R4—K—R4—]n, each being optionally substituted with R5;each R4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;each K is O, S, SO, SO2, CO, CO2, or CONR3;each R5 is independently halogen, alkyl, —OR6, —N(R6)2, —SR6, —SOR6, —SO2R6, —CO2R6, a fluorescent moiety, a radioisotope or a therapeutic agent;each R6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;R7 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with a D residue;R8 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, 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; andn 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-L3-CO—], [—NH-L3-SO2], or [—NH-L3];R1 and R2 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;R3 is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5;L1 and L2 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R4—K—R4—]n, each being optionally substituted with R5;each R4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;each K is O, S, SO, SO2, CO, CO2, or CONR3;each R5 is independently halogen, alkyl, —OR6, —N(R6)2, —SR6, —SOR6, —SO2R6, —CO2R6, a fluorescent moiety, a radioisotope or a therapeutic agent;each R6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;R7 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5;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; andn is an integer from 1-5. 15. The peptidomimetic macrocycle of claim 14, wherein L1 and L2 either alone or in combination do not include a thioether or a triazole. 16. The peptidomimetic macrocycle of claim 11, wherein L1 and L2 are independently alkylene, alkenylene or alkynylene. 17. The peptidomimetic macrocycle of claim 11, wherein L1 and L2 are independently C3-C10 alkylene or alkenylene. 18. The peptidomimetic macrocycle of claim 17, wherein L1 and L2 are independently C3-C6 alkylene or alkenylene. 19. The peptidomimetic macrocycle of claim 11, wherein R1 and R2 are H. 20. The peptidomimetic macrocycle of claim 11, wherein R1 and R2 are independently alkyl. 21. The peptidomimetic macrocycle of claim 11, wherein R1 and R2 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.
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