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Originally published In Press as doi:10.1074/jbc.M110758200 on January 22, 2002

J. Biol. Chem., Vol. 277, Issue 15, 12596-12603, April 12, 2002
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Structural Determinants for HIV-1 Integrase Inhibition by beta -Diketo Acids*

Christophe MarchandDagger , Xuechun Zhang§, Godwin C. G. Pais§, Kiriana CowansageDagger , Nouri Neamati, Terrence R. Burke Jr.§, and Yves PommierDagger ||

From the Dagger  Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892-4255, the § Laboratory of Medicinal Chemistry, Center for Cancer Research, NCI, Frederick, Maryland 21702, and the  College of Pharmacy, University of Southern California, Los Angeles, California 90089-9121

Among all the HIV-1 integrase inhibitors, the beta -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 has been to investigate the molecular interactions between DKAs and HIV-1 integrase. We have 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 that 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.

* The costs of publication of this article were defrayed in part by the payment of page charges. The 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: Bldg. 37, Rm. 5068, Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, MD 20892-4255. Tel.: 301-496-5944; Fax: 301-402-0752; E-mail: pommier@nih.gov.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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