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J. Biol. Chem., Vol. 281, Issue 43, 32428-32438, October 27, 2006

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Effect of DNA Modifications on DNA Processing by HIV-1 Integrase and Inhibitor Binding

ROLE OF DNA BACKBONE FLEXIBILITY AND AN OPEN CATALYTIC SITE^*

Allison A. Johnson, Jane M. Sayer, Haruhiko Yagi, Sachindra S. Patil^¶, Françoise Debart^||, Martin A. Maier^**, David R. Corey, Jean-Jacques Vasseur^||, Terrence R. Burke, Jr.^¶, Victor E. Marquez^¶, Donald M. Jerina, and Yves Pommier¹

From the Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, ^¶Laboratory of Medicinal Chemistry, Center for Cancer Research, NCI-Frederick, National Institutes of Health, Department of Health and Human Services, Frederick, Maryland 20892, ^||LCOBS UMR 5625 CNRS-Université Montpellier II, 34095 Montpellier, France, ^**Isis Pharmaceuticals, Inc., Carlsbad, California 92008, and Departments of Pharmacology and Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75235

Integration of the viral cDNA into host chromosomes is required for viral replication. Human immunodeficiency virus integrase catalyzes two sequential reactions, 3'-processing (3'-P) and strand transfer (ST). The first integrase inhibitors are undergoing clinical trial, but interactions of inhibitors with integrase and DNA are not well understood in the absence of a co-crystal structure. To increase our understanding of integrase interactions with DNA, we examined integrase catalysis with oligonucleotides containing DNA backbone, base, and groove modifications placed at unique positions surrounding the 3'-processing site. 3'-Processing was blocked with substrates containing constrained sugars and -anomeric residues, suggesting that integrase requires flexibility of the phosphodiester backbone at the 3'-P site. Of several benzo[a]pyrene 7,8-diol 9,10-epoxide (BaP DE) adducts tested, only the adduct in the minor groove at the 3'-P site inhibited 3'-P, suggesting the importance of the minor groove contacts for 3'-P. ST occurred in the presence of bulky BaP DE DNA adducts attached to the end of the viral DNA suggesting opening of the active site for ST. Position-specific effects of these BaP DE DNA adducts were found for inhibition of integrase by diketo acids. Together, these results demonstrate the importance of DNA structure and specific contacts with the viral DNA processing site for inhibition by integrase inhibitors.

Received for publication, May 30, 2006 , and in revised form, July 13, 2006.

^* This work was supported by the Intramural Research Program of the NCI, Center for Cancer Research, and of the NIDDK, National Institutes of Health, National Institutes of Health Grant GM60642 (to D. R. C.), and CNRS (to J. J. V. and F. D.). 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.

The on-line version of this article (available at http://www.jbc.org) contains additional text and supplemental Table 1.

¹ To whom correspondence should be addressed: Laboratory of Molecular Pharmacology, Bldg. 37, Rm. 5068, National Institutes of Health, Bethesda, MD 20892. Tel.: 301-496-5944; Fax: 301-402-0752; E-mail: pommier{at}nih.gov.

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