Section Reviews; Anti-infectives: Section Review Anti-infectives: Therapeutic potential of nonnucleoside reverse transcriptase inhibitors in the treatment of HIV infection

Abstract

Nonnucleoside inhibitors are one class of drugs currently in clinical trial for the treatment of AIDS. These compounds are structurally diverse, but all bind tightly and specifically to a hydrophobic region on HIV-1 reverse transcriptase (RT). This review describes the role of nonnucleoside inhibitors with respect to the structure and function of HIV-1 reverse transcriptase. It has been determined that the binding of these inhibitors induces a distortion at the polymerase active site which inhibits the chemical step of nucleotide incorporation. However, accumulation of mutant RT enzymes which are resistant to these nonnucleoside inhibitors limits the therapeutic value of monotherapy. Rapid development of drug-resistant RT enzymes suggests that the residues promoting the tight binding of the inhibitors are also nonessential for RT activity. Current efforts toward the use of these drugs are predominantly through combination therapy involving other HIV inhibitors. Coordinating a multi-drug regimen is complicated by the fact that resistant RT mutants that are isolated in single drug treatment often do not agree with those isolated in combination therapy. The current potential of nonnucleoside inhibitors lies in their low cytotoxicity, allowing them to be administered at high concentrations. Continuation of biochemical studies will facilitate the design of HIV RT inhibitors that target essential resldues, whereupon resistance cannot develop without the emergence of a nonfunctional enzyme.