Discovery of small molecular inhibitors targeting HIV-1 gp120–CD4 interaction drived from BMS-378806

•The gp120–CD4 interaction represented a promising anti-HIV therapeutic target.•BMS-378806 derivatives were newly identified class of gp120–CD4 interaction inhibitors.•The SARs and drug-like profiles of BMS-378806 and its analogues were reviewed.•The structural modifications of NBD-556 targeting the “Phe-43 cavity” were described.

The HIV-1 entry into host cells is a complex, multi-factors involved, and multi-step process. Especially, the attachment of HIV-1 envelope glycoprotein gp120 to the host cell receptor CD4 is the first key step during entry process, representing a promising antiviral therapeutic target. Among the HIV-1 attachment inhibitors blocking the interaction between gp120 and CD4 cells, BMS-378806 and NBD-556 are two representative small molecular chemical entities. Particularly, BMS-378806 and its derivatives are newly identified class of orally bioavailable HIV-1 inhibitors that interfere gp120–CD4 interaction. In this review, we focused on describing the structure–activity relationships (SARs), structural modifications, in vitro or even in vivo pharmacodynamics and pharmacokinetics of BMS-378806 and its analogues as HIV-1 gp120 attachment inhibitors. In addition, the brief SARs, structural modifications of NBD-556 and its derivatives targeting the “Phe-43 cavity” as CD4 mimics were also described.

Graphical abstractBMS-378806 and its derivatives were identified as novel class of orally bioavailable HIV-1 inhibitors that interfere gp120–CD4 interaction.Figure optionsDownload full-size imageDownload as PowerPoint slide