HIV Capsid is a Tractable Target for Small Molecule Therapeutic Intervention

Luban, Jeremy and Blair, Wade S. and Pickford, Chris and Irving, Stephen L. and Brown, David G. and Anderson, Marie and Bazin, Richard and Cao, Joan and Ciaramella, Giuseppe and Isaacson, Jason and Jackson, Lynn and Hunt, Rachael and Kjerrstrom, Anne and Nieman, James A. and Patick, Amy K. and Perros, Manos and Scott, Andrew D. and Whitby, Kevin and Wu, Hua and Butler, Scott L. (2010) HIV Capsid is a Tractable Target for Small Molecule Therapeutic Intervention. PLoS Pathogens, 6 (12). e1001220. ISSN 1553-7374. (The full text of this publication is not available from this repository)

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Official URL
http://dx.doi.org/10.1371/journal.ppat.1001220

Abstract

Despite a high current standard of care in antiretroviral therapy for HIV, multidrug-resistant strains continue to emerge, underscoring the need for additional novel mechanism inhibitors that will offer expanded therapeutic options in the clinic. We report a new class of small molecule antiretroviral compounds that directly target HIV-1 capsid (CA) via a novel mechanism of action. The compounds exhibit potent antiviral activity against HIV-1 laboratory strains, clinical isolates, and HIV-2, and inhibit both early and late events in the viral replication cycle. We present mechanistic studies indicating that these early and late activities result from the compound affecting viral uncoating and assembly, respectively. We show that amino acid substitutions in the N-terminal domain of HIV-1 CA are sufficient to confer resistance to this class of compounds, identifying CA as the target in infected cells. A high-resolution co-crystal structure of the compound bound to HIV-1 CA reveals a novel binding pocket in the N-terminal domain of the protein. Our data demonstrate that broad-spectrum antiviral activity can be achieved by targeting this new binding site and reveal HIV CA as a tractable drug target for HIV therapy.

Item Type: Article
Subjects: Q Science
Divisions: Faculties > Science Technology and Medical Studies > School of Biosciences
Depositing User: Sue Davies
Date Deposited: 08 Oct 2012 11:04
Last Modified: 30 Jan 2013 11:34
Resource URI: http://kar.kent.ac.uk/id/eprint/31353 (The current URI for this page, for reference purposes)
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