Structural Basis for the Resilience of Efavirenz (DMP-266) to Drug Resistance Mutations in HIV-1 Reverse Transcriptase

• Published in: Structure (London) Vol. 8; no. 10; pp. 1089 - 1094
• Main Authors: Ren, Jingshan, Milton, John, Weaver, Kurt L., Short, Steven A., Stuart, David I., Stammers, David K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-10-2000
• Subjects: Amino Acid Substitution - genetics; Anti-HIV Agents - chemistry; Anti-HIV Agents - metabolism; Anti-HIV Agents - pharmacology; Benzoxazines; Binding Sites; Crystallography, X-Ray; drug resistance; Drug Resistance, Microbial - genetics; efavirenz; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - chemistry; HIV Reverse Transcriptase - genetics; HIV Reverse Transcriptase - metabolism; HIV-1; HIV-1 - drug effects; HIV-1 - enzymology; HIV-1 - genetics; Humans; Models, Molecular; Mutation - genetics; nevirapine; Nevirapine - chemistry; Nevirapine - metabolism; Nevirapine - pharmacology; Oxazines - chemistry; Oxazines - metabolism; Oxazines - pharmacology; Protein Binding; Protein Conformation; reverse transcriptase; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - metabolism; Reverse Transcriptase Inhibitors - pharmacology; Structure-Activity Relationship; HIV-1; nevirapine; drug resistance; reverse transcriptase; efavirenz
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/S0969-2126(00)00513-X

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.