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J. Biol. Chem., Vol. 282, Issue 44, 32406-32413, November 2, 2007

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A Covalent Inhibitor Targeting an Intermediate Conformation of the Fusogenic Subunit of the HIV-1 Envelope Complex^*

Amy Jacobs, Omar Quraishi¹, Xicai Huang, Nathalie Bousquet-Gagnon, Geneviève Nault, Nicholas Francella, W. Gregory Alvord^¶, Nga Pham, Chantal Soucy, Martin Robitaille, Dominique Bridon, and Robert Blumenthal²

From the Center for Cancer Research Nanobiology Program, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702, Conjuchem Biotechnologies, Inc., Montreal, Quebec H2X 3Y8, Canada, and ^¶Data Management Services, Inc., NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702

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.

Received for publication, July 6, 2007 , and in revised form, August 20, 2007.

^* This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Conjuchem Biotechnologies Inc., 225 President Kennedy Ave., Ste. PK-3950, Montreal, Quebec H2X 3Y8, Canada. Tel.: 514-844-5558; Fax: 514-844-1119; E-mail: quraishi{at}conjuchem.com.

² To whom correspondence may be addressed: Center for Cancer Research Nanobiology Program, NCI, National Institutes of Health, Frederick, MD 21702. Tel.: 301-846-5532; Fax: 301-846-5598; E-mail: blumenthalr{at}mail.nih.gov.

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