Faculty of Education

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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: TAKAHIRO SOETA)

Journal of Medicinal Chemistry. 2012;55(9):4382-4396.

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. © 2012 American Chemical Society.

PMID: 22497421     PMCID: PMC3376652

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