Structure-Based Design, Synthesis, and Characterization of Dual Hotspot Small-Molecule HIV-1 Entry Inhibitors

Journal Article · Tue Jun 19 04:00:00 EDT 2012 · J. Med. Chem.

DOI:https://doi.org/10.1021/jm300265j· OSTI ID:1041338

LaLonde, Judith M; Kwon, Young Do; Jones, David M; Sun, Alexander W; Courter, Joel R; Soeta, Takahiro; Kobayashi, Toyoharu; Princiotto, Amy M; Wu, Xueling; Schön, Arne; Freire, Ernesto; Kwong, Peter D; Mascola, John R; Sodroski, Joseph; Madani, Navid

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{sub CD4} and an electrostatic interaction between residues Arg59{sub CD4} and Asp368{sub 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.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: NIHNIAID
• OSTI ID: 1041338
• Journal Information: J. Med. Chem., Journal Name: J. Med. Chem. Journal Issue: (9) ; 05, 2012 Vol. 55; ISSN JMCMAR; ISSN 0022-2623
• Country of Publication: United States
• Language: ENGLISH

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