Peptidomimetic macrocycles

A method of antagonizing the interaction between a p53 protein and a HDM2 protein, between a p53 protein and a HDMX protein, or a combination thereof, in a subject comprising administering to the subject a therapeutically-effective amount of a peptidomimetic macrocycle, wherein the peptidomimetic macrocycle comprises an amino acid sequence which is at least 60% identical to an amino acid sequence selected from the group consisting of:

• SEQ ID NO 289, SEQ ID NO 290, SEQ ID NO 374, SEQ ID NO 375, SEQ ID NO 507, SEQ ID NO 533, SEQ ID NO 587, SEQ ID NO 624, SEQ ID NO 642, SEQ ID NO 699, SEQ ID NO 702, SEQ ID NO 703, SEQ ID NO 704, SEQ ID NO 714, SEQ ID NO 734, and SEQ ID NO 742,
• wherein the peptidomimetic macrocycle has the formula:
• wherein:
• each A, C, D, and E is independently a natural or non-natural amino acid, and each D and E independently optionally includes a capping group;
• each B is independently a natural or non-natural amino acid, amino acid analog, or
• each R1 and R2 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-;
• each R3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5;
• each L is independently a macrocycle-forming linker of the formula -L1-L2-;
• each L1 and L2 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R4—K—R4-]n, each optionally substituted with R5;
• each R4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
• each K is independently 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;
• each R7 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, each optionally substituted with R5, or forms part of a cyclic structure with a D residue;
• each R8 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, each optionally substituted with R5, or forms part of a cyclic structure with an E residue;
• each v and w is independently an integer from 1-1000;
• u is an integer from 1-10;
• each x, y and z is independently an integer from 0-10, wherein x+y+z is 6;
• and
• each n is independently an integer from 1-5.