Small-molecule HIV-1 gp120 inhibitors to prevent HIV-1 entry: an emerging opportunity for drug development.

The HIV-1 gp120 envelope protein is an essential component in the multi-tiered viral entry process. Despite the overall genetic heterogeneity of the gp120 glycoprotein, the conserved CD4 binding site provides an attractive antiviral target. Recently, increased efforts aimed at the development of inhibitors of gp120 have been reported. This review focuses primarily on small-molecule gp120 inhibitors and discusses key characteristics of compounds that appear to fall within this class. The preclinical profiles of compounds that prevent gp120 from assuming a conformation favorable for CD4 binding are described in this review. In addition, inhibitors possessing some common structural features, including at least one compound that exhibits sub-nanomolar potency in a cell fusion assay are discussed. A series of compounds that were designed to enhance immune responses to virus via alteration of the gp120 conformation after targeting the CD4 binding pocket are also described. The efficacy of gp120 inhibitors as a microbicide to prevent sexual HIV transmission in the rhesus macaque model is discussed. Results suggest that this class of compounds may have value if included in a microbicide cocktail with inhibitors of alternate mechanisms. Importantly, preliminary results from clinical studies of orally administered BMS-488043 demonstrate that antiviral efficacy can be achieved in humans with a CD4-attachment inhibitor that targets gp120.