Patent ID: 8609809

Claim:
A method for synthesizing a peptidomimetic macrocycle, comprising contacting a peptidomimetic precursor of Formula III: with a compound of formula X-L 2 -Y, wherein each A, C, D, and E is independently a natural or non-natural amino acid; B is a natural or non-natural amino acid, amino acid analog, [—NH-L 4 -CO—], [—NH-L 4 -SO 2 —], or [—NH-L 4 -]; R 1 and R 2 are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, each of which except —H is unsubstituted or substituted with halo-; R 3 is —H, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, each of which except —H is unsubstituted or substituted with R 5 ; L 1 , L 3 , and L 4 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R 4 —K—R 4 —] n , each being unsubstituted or substituted with R 5 ; L 2 is cycloalkylene, cycloarylene or heterocycloarylene, each of which is unsubstituted or substituted with R 5 ; K is O, S, SO, SO 2 , CO, CO 2 , or CONR 3 ; each R 4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; 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, each of which except —H is unsubstituted or 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, each of which except —H is unsubstituted or substituted with R 5 , 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; n is an integer from 1-5; X and Y are each independently a reactive group capable of reacting with a thiol group; and x+y+z is at least 3, wherein the contacting results in a covalent linkage being formed between the two thiol groups in Formula III, and wherein the peptidomimetic macrocycle exhibits increased resistance to proteolytic degradation compared to a corresponding non-macrocyclic polypeptide; further wherein the peptidomimetic macrocycle comprises an α-helix when in aqueous solution.