Format

Send to

Choose Destination
See comment in PubMed Commons below
J Med Chem. 2012 May 10;55(9):4382-96. doi: 10.1021/jm300265j. Epub 2012 Apr 23.

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

Author information

1
Department of Chemistry, Bryn Mawr College, Bryn Mawr, Pennsylvania 19010, USA. jlalonde@brynmawr.edu

Abstract

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.

PMID:
22497421
PMCID:
PMC3376652
DOI:
10.1021/jm300265j
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for American Chemical Society Icon for PubMed Central
    Loading ...
    Support Center