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Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase, RNase H, and Integrase Activities by Hydroxytropolones

Unité Propre de Recherche 9002 du CNRS conventionnée à l'Université Louis Pasteur, IBMC, 15 rue René Descartes, 67084 Strasbourg cedex, France,¹ Laboratoire des Fonctions Azotées et Oxygénées Complexes, Unité Mixte de Recherche 6014 du CNRS, IRCOF, Université de Rouen, rue Tesnière, 76821 Mont St. Aignan cedex, France,² LBPA, Unité Mixte de Recherche 8113 du CNRS, Ecole Normale Supérieure de Cachan, 61 avenue du Président Wilson, 94235 Cachan, France,³ Unité Mixte de Recherche 544 INSERM—Université Louis Pasteur, Institut de Virologie, 67000 Strasbourg, France⁴

Received 18 January 2005/ Returned for modification 18 March 2005/ Accepted 13 September 2005

Human immunodeficiency virus type I reverse transcriptase (RT) possesses distinct DNA polymerase and RNase H sites, whereas integrase (IN) uses the same active site to perform 3'-end processing and strand transfer of the proviral DNA. These four enzymatic activities are essential for viral replication and require metal ions. Two Mg²⁺ ions are present in the RT polymerase site, and one or two Mg²⁺ ions are required for the catalytic activities of RNase H and IN. We tested the possibility of inhibition of the RT polymerase and RNase H as well as the IN 3'-end processing and transfer activities of purified enzymes by a series of 3,7-dihydroxytropolones designed to target two Mg²⁺ ions separated by 3.7 Å. The RT polymerase and IN 3' processing and strand transfer activities were inhibited at submicromolar concentrations, while the RNase H activity was inhibited in the low micromolar range. In all cases, the lack of inhibition by tropolones and O-methylated 3,7-dihydroxytropolones was consistent with the active molecules binding the metal ions in the active site. In addition, inhibition of the DNA polymerase activity was shown to depend on the Mg²⁺ concentration. Furthermore, selective inhibitors were identified for several of the activities tested, leaving some potential for design of improved inhibitors. However, all tested compounds exhibited cellular toxicity that presently limits their applications.

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