A covalent inhibitor targeting an intermediate conformation of the fusogenic subunit of the HIV-1 envelope complex

doi:10.1074/jbc.M705577200

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Papers In Press, published online ahead of print August 28, 2007
J. Biol. Chem, 10.1074/jbc.M705577200
Submitted on July 6, 2007
Revised on August 20, 2007
Accepted on August 28, 2007

A covalent inhibitor targeting an intermediate conformation of the fusogenic subunit of the HIV-1 envelope complex

Amy Jacobs, Omar Quraishi, Xicai Huang, Nathalie Bousquet-Gagnon, Genevieve Nault, Nicholas Francella, W. Gregory Alvord, Nga Pham, Chantal Soucy, Martin Robitaille, Dominique Bridon, and Robert Blumenthal

CCR Nanobiology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702

Corresponding Author: BlumenthalR{at}mail.nih.gov

Peptide inhibitors corresponding to sequences in the six helix bundle structure of the fusogenic portion (gp41) of the HIV envelope glycoprotein have been successfully implemented in preventing HIV entry. These peptides bind to regions in HIV gp41 transiently exposed during the fusion reaction. In an effort to improve upon these entry inhibitors, we have successfully designed and tested peptide analogs composed of chemical spacers and reactive moieties positioned strategically to facilitate covalent attachment. Using a temperature-arrested state prime-wash in vitro assay we show evidence for the trapping of a pre-six helix bundle fusion intermediate by a covalent reaction with the specific anti-HIV-1 peptide. This is the first demonstration of the trapping of an intermediate conformation of a viral envelope glycoprotein during the fusion process that occurs in live cells. The permanent specific attachment of the covalent inhibitor is projected to improve the pharmacokinetics of administration in vivo and thereby improve the long-term sustainability of peptide entry inhibitor therapy and help to expand its applicability beyond salvage therapy.

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