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A more recent version of this article appeared on April 5, 2002
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M110758200v1
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Papers In Press, published online ahead of print January 22, 2002
J. Biol. Chem, 10.1074/jbc.M110758200
Submitted on November 8, 2001
Revised on January 11, 2002
Accepted on January 18, 2002

Structural determinants for HIV-1 integrase inhibition by b-diketo acids

Christophe Marchand, Xuechun Zhang, Godwin C.G. Pais, Kiriana Cowansage, Nouri Neamati, Terrence R. Burke Jr, and Yves Pommier

Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, Maryland 20892

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

Among all the HIV-1 integrase inhibitors, the b-diketo acids (DKAs) represent a major lead in anti-HIV-1 integrase drug design. These derivatives inhibit the integration reaction in vitro with a strong specificity for the 3’-end joining step. They are also antiviral and inhibit integration in vivo. The aim of the present study was to investigate the molecular interactions between DKAs and HIV-1 integrase. We compared 5CITEP with one of the most potent DKAs reported by the Merck group (L-708,906) and found that 5CITEP inhibits 3’-processing at concentrations where L-708,906 is only active on strand transfer. We also report a novel bifunctional DKA derivative, which inhibits 3’-processing even more effectively than 5CITEP. The interactions of these inhibitors with the viral DNA donor ends have been studied by performing experiments with oligonucleotides containing defined modifications. We propose that the bifunctional DKA derivative binds to both the acceptor and donor sites of HIV-1 integrase whereas, the monofunctional L-708,906 derivative binds selectively to the acceptor site.


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