Beschreibung:
<jats:title>ABSTRACT</jats:title>
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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 Mg
<jats:sup>2+</jats:sup>
ions are present in the RT polymerase site, and one or two Mg
<jats:sup>2+</jats:sup>
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 Mg
<jats:sup>2+</jats:sup>
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 Mg
<jats:sup>2+</jats:sup>
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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