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First published on January 17, 2006; DOI: 10.1124/mol.105.020321

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Received for publication October 31, 2005.
Revised December 22, 2005.
Accepted for publication January 17, 2006.

Preferential Inhibition of the Magnesium-Dependent Strand Transfer Reaction of HIV-1 Integrase by {alpha}-Hydroxytropolones

Elena A Semenova 1, Allison A Johnson 1, Christophe Marchand 1, David A Davis 2, Robert Yarchoan 2, Yves Pommier 1*

1 Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH 2 HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, NIH

* Address correspondence to: E-mail: pommier{at}nih.gov

Abstract

Integration is a crucial step in the life cycle of human immunodeficiency virus type 1 (HIV-1), and therefore inhibitors of HIV-1 integrase are candidates for antiretroviral therapy. Two 7-hydroxytropolone derivatives ({alpha}-hydroxytropolones) were found to inhibit HIV-1 integrase. A structure-activity relationship investigation with several tropolone derivatives from The National Cancer Institute compound repository demonstrated that the 7-hydroxy group is essential for integrase inhibition. {alpha}-hydroxytropolones preferentially inhibit strand transfer and are inhibitory both in the presence of magnesium or manganese. Lack of inhibition of disintegration in the presence of magnesium coupled with results from different crosslinking assays suggests {alpha}-hydroxytropolones as interfacial inhibitors. We propose that {alpha}-hydroxytropolones chelate the divalent metal (Mg2+ or Mn2+) in the enzyme active site. The most active compound against HIV-1 integrase in biochemical assays (NSC 18806, IC50 = 4.8 ± 2.5 µM) exhibits weak cytoprotective activity against HIV-1IIIB in a cell-based assay. {alpha}-hydroxytropolones represent a new family of inhibitors for the development of novel drugs against HIV infection.


Key words: Enzymology, Structure/function/mechanism, Antiviral drugs


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