1c1b

Publication Abstract from PubMed

Two analogues of the nonnucleoside inhibitor of HIV-1 RT, MKC-442 (emivirine), containing different C6 substituents have been designed to be less susceptible to the commonly found drug-resistance mutation of Tyr181Cys. Compound TNK-6123 had a C6 thiocyclohexyl group designed to have more flexibility in adapting to the mutated drug-binding site. GCA-186 had additional 3',5'-dimethyl substituents aimed at forming close contacts with the conserved residue Trp229. Both compounds showed approximately 30-fold greater inhibitory effect than MKC-442 to the Tyr181Cys mutant virus as well as to the clinically important Lys103Asn virus. X-ray crystallographic structure determination of complexes with HIV-1 RT confirmed the predicted binding modes. These strategies might be used to improve the resilience of other NNRTI series against common drug-resistance mutations.

Design of MKC-442 (emivirine) analogues with improved activity against drug-resistant HIV mutants.,Hopkins AL, Ren J, Tanaka H, Baba M, Okamato M, Stuart DI, Stammers DK J Med Chem. 1999 Nov 4;42(22):4500-5. PMID:10579814^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.