Patent ID: 8808694

Claim:
A method of selecting a peptidomimetic macrocycle that generates a reduced antibody response capable of being used in therapy to treat a cell proliferative disorder, comprising: a) preparing a peptidomimetic macrocycle by forming a cross-linker connecting two amino acid residues of a polypeptide to stabilize a secondary structure of the peptidomimetic macrocycle; b) testing the peptidomimetic macrocycle for a reduced antibody response in an in vivo assay as compared to a corresponding uncross-linked polypeptide; and c) selecting the tested peptidomimetic macrocycle as the peptidomimetic macrocycle that generates the reduced antibody response capable of being used in therapy to treat a cell proliferative disorder if the tested peptidomimetic macrocycle has the reduced antibody response; and wherein the peptidomimetic macrocycle that generates the reduced antibody response is of Formula (I): 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 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, each of which except —H is unsubstituted or substituted with halo-; R 3 is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, each of which except hydrogen is optionally substituted with R 5 ; L is a macrocycle-forming linker of the formula -L 1 -L 2 -; L 1 and L 2 and L 3 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 independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; each K is independently 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, each of which except —H is 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, each of which except —H is optionally substituted with R 5 , or part of a cyclic structure with an E residue; each of v and w is independently an integer from 1-1000; each of x, y, and z, is independently an integer from 0-10; u is an integer from 1-10; and n is an integer from 1-5.