Anti-AIDS drug development: challenges and strategies

A myriad of chemical derivatives has been shown to inhibit in vitro replication of the AIDS virus at concentrations that are nontoxic to the host cells. The majority of these agents acts by either (i) inhibiting enzymes such as reverse transcriptase (RT), protease, or glucosidase, (ii) arresting expression of genes or gene products, or (iii) inhibiting viral processes such as giant cell (syncytia) formation or viral binding to the target cell. The nucleoside RT inhibitors are the most widely studied agents at both the preclinical and the clinical levels. Their inability to cure AIDS has stimulated the discovery of several novel nonnucleoside RT inhibitors, possessing varied structures and demonstrating activity at nanomolar concentrations. These agents demonstrate a unique mode of binding to RT and show a high specificity for HIV-1. Protease inhibitors, soluble CD4 derivatives, oligonucleotides, and many anionic derivatives also demonstrate potent anti-HIV-1 activities. These derivatives possess mechanisms of action different to the nucleosides and exhibit selectivity as exemplified by their high in vitro therapeutic indices. This article discusses the structural parameters that govern activity in these agents, the pros and cons regarding the development of these compounds as putative anti-AIDS agents, and the future promise of searching for newer agents directed at novel targets to inhibit the AIDS virus.