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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.

Type

Journal article

Journal

J Med Chem

Publication Date

04/11/1999

Volume

42

Pages

4500 - 4505

Keywords

Animals, Anti-HIV Agents, Cell Line, Crystallography, X-Ray, Drug Design, Drug Resistance, Microbial, HIV-1, Models, Molecular, Molecular Conformation, Mutation, Reverse Transcriptase Inhibitors, Uracil