Ernesto Freire

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Structure-based design, synthesis, and characterization of dual hotspot small-molecule HIV-1 entry inhibitors.

Judith M LaLonde; Young Do Kwon; David M Jones; Alexander W Sun; Joel R Courter; Takahiro Soeta; Toyoharu Kobayashi; Amy M Princiotto; Xueling Wu; Arne Schön; et al. (Profiled Author: Ernesto Freire)

Department of Chemistry, Bryn Mawr College, Bryn Mawr, Pennsylvania 19010, USA. jlalonde@brynmawr.edu
Journal of medicinal chemistry 2012;55(9):4382-96.

Cellular infection by HIV-1 is initiated with a binding event between the viral envelope glycoprotein gp120 and the cellular receptor protein CD4. The CD4-gp120 interface is dominated by two hotspots: a hydrophobic gp120 cavity capped by Phe43(CD4) and an electrostatic interaction between residues Arg59(CD4) and Asp368(gp120). The CD4 mimetic small-molecule NBD-556 (1) binds within the gp120 cavity; however, 1 and related congeners demonstrate limited viral neutralization breadth. Herein, we report the design, synthesis, characterization, and X-ray structures of gp120 in complex with small molecules that simultaneously engage both binding hotspots. The compounds specifically inhibit viral infection of 42 tier 2 clades B and C viruses and are shown to be antagonists of entry into CD4-negative cells. Dual hotspot design thus provides both a means to enhance neutralization potency of HIV-1 entry inhibitors and a novel structural paradigm for inhibiting the CD4-gp120 protein-protein interaction.

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