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J. Biol. Chem., Vol. 280, Issue 12, 11259-11273, March 25, 2005

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Different from the HIV Fusion Inhibitor C34, the Anti-HIV Drug Fuzeon (T-20) Inhibits HIV-1 Entry by Targeting Multiple Sites in gp41 and gp120^*

Shuwen Liu, Hong Lu, Jinkui Niu, Yujia Xu, Shuguang Wu¶, and Shibo Jiang||

From the Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York 10021, the Department of Chemistry, Hunter College, City University of New York, New York, New York 10021, and the ^¶Institute of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China

Fuzeon (also known as T-20 or enfuvirtide), one of the C-peptides derived from the HIV-1 envelope glycoprotein transmembrane subunit gp41 C-terminal heptad repeat (CHR) region, is the first member of a new class of anti-HIV drugs known as HIV fusion inhibitors. It has been widely believed that T-20 shares the same mechanism of action with C34, another C-peptide. The C34 is known to compete with the CHR of gp41 to form a stable 6-helix bundle (6-HB) with the gp41 N-terminal heptad repeat (NHR) and prevent the formation of the fusogenic gp41 core between viral gp41 NHR and CHR, thereby inhibiting fusion between viral and target cell membranes. Here we present data to demonstrate that, contrary to this belief, T-20 cannot form stable 6-HB with N-peptides derived from the NHR region, nor can it inhibit the 6-HB formation of the fusogenic core. Instead, it may interact with N-peptides to form unstable or insoluble complexes. Our data suggest that T-20 has a different mechanism of action from C34. The interaction of T-20 with viral NHR region alone may not prevent the formation of the fusion active gp41 core. We also demonstrate that the T-20-mediated anti-HIV activity can be significantly abrogated by peptides derived from the membrane-spanning domain in gp41 and coreceptor binding site in gp120. These new findings imply that T-20 inhibits HIV-1 entry by targeting multiple sites in gp41 and gp120. Further elucidation of the mechanism of action of T-20 will provide new target(s) for development of novel HIV entry inhibitors.

Received for publication, September 28, 2004 , and in revised form, January 4, 2005.

^* This work was supported by Grant AI46221 from the National Institutes of Health (to S. J.) and Grants from the 863 Project Foundation of China (2001AA214201) and Natural Science Foundation of China (301400220) (to S. W.). 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.

^|| To whom correspondence should be addressed: The Lindsley F. Kimball Research Institute, NY Blood Center, New York, NY 10021. Tel.: 1-212-570-3058; Fax: 1-212-570-3099; E-mail: sjiang{at}nybloodcenter.org.

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