Bis-sulfhydryl macrocyclization systems

A method of inhibiting mouse double minute 2 homolog (MDM2) or mouse double minute X homolog (MDMX) activity in a subject, the method comprising administering to the subject a peptidomimetic macrocycle of Formula (I):

• wherein:
• each A, C, D, and E is independently a natural or non-natural amino acid;
• each B is independently a natural or non-natural amino acid, amino acid analog,
• [—NH-L4-CO—], [—NH-L4-SO2—], or [—NH-L4-];
• R1 and R2 are 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, cycloalkyl alkyl, cycloaryl, or heterocycloaryl, unsubstituted or substituted with R5;
• L1, L3 and L4 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene or [—R4—K—R4-]n, each being unsubstituted or substituted with R5;
• L2 is alkylene, alkenylene, alkynylene, heteroalkylene, heterocycloalkylene, or [—K—R4]n, each being unsubstituted or substituted with R5;
• each K is independently O, S, SO, SO2, CO, CO2, or CONR3;
• each R4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
• 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, unsubstituted or 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, unsubstituted or substituted with R5, or part of a cyclic structure with an E residue;
• v is an integer from 1-1000;
• w is an integer from 1-1000;
• x is an integer from 0-10;
• y is an integer from 0-10;
• z is an integer from 0-10;
• and
• n is an integer from 1-5.