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

Background: Efavirenz is a second-generation non-nucleoside inhibitor of HI V-1 reverse transcriptase (RT) that has recently been approved for use agai nst HIV-1 infection. Compared with first-generation drugs such as nevirapin e, efavirenz shows greater resilience to drug resistance mutations within H IV-1 RT. In order to understand the basis for this resilience at the molecu lar level and to help the design of further-improved anti-AIDS drugs, we ha ve 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, with in 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 th e 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 protei n, could represent a general mechanism whereby certain second-generation no n-nucleoside inhibitors are able to reduce the effect of drug-resistance mu tations on binding potency.