Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase.

Journal article

BACKGROUND: Efavirenz is a second-generation non-nucleoside inhibitor of HIV-1 reverse transcriptase (RT) that has recently been approved for use against HIV-1 infection. Compared with first-generation drugs such as nevirapine, efavirenz shows greater resilience to drug resistance mutations within HIV-1 RT. In order to understand the basis for this resilience at the molecular level and to help the design of further-improved anti-AIDS drugs, we have determined crystal structures of efavirenz and nevirapine with wild-type RT and the clinically important K103N mutant. RESULTS: The relatively compact efavirenz molecule binds, as expected, within the non-nucleoside inhibitor binding pocket of RT. There are significant rearrangements of the drug binding site within the mutant RT compared with the wild-type enzyme. These changes, which lead to the repositioning of the inhibitor, are not seen in the interaction with the first-generation drug nevirapine. CONCLUSIONS: The repositioning of efavirenz within the drug binding pocket of the mutant RT, together with conformational rearrangements in the protein, could represent a general mechanism whereby certain second-generation non-nucleoside inhibitors are able to reduce the effect of drug-resistance mutations on binding potency.

Authors: Ren, J; Milton, J; Weaver, K; Short, SA; Stuart, D

• Publication status: Published
• Journal: Structure (London, England : 1993)
• Volume: 8
• Issue: 10
• Pages: 1089-1094
• Publication date: 2000-10-01
• DOI: 10.1016/s0969-2126(00)00513-x
• EISSN: 1878-4186
• ISSN: 0969-2126
• Language: English
• Keywords: Drug Resistance, Microbial; Anti-HIV Agents; HIV-1; Oxazines; Reverse Transcriptase Inhibitors; Humans; Protein Conformation; Crystallography, X-Ray; Benzoxazines; Binding Sites; Structure-Activity Relationship; HIV Reverse Transcriptase; Models, Molecular; Mutation; Protein Binding; Nevirapine; Amino Acid Substitution