nbd-557 and HIV-Infections

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.

Topics: Calorimetry; CD4 Antigens; Crystallography, X-Ray; HIV Envelope Protein gp120; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Indans; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Mass Spectrometry; Models, Molecular; Molecular Dynamics Simulation; Neutralization Tests; Structure-Activity Relationship; Thermodynamics; Virus Internalization