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Centre National de la Recherche Scientifique Unité Mixte Recherche 8113, Laboratoire de Biotechnologies et Pharmacologie génétique Appliquée, Ecole Normale Supérieure de Cachan, Cachan, France (E.D., S.B., M.K., C.A., J.-C.B., M.L.B., J.-F.M.); and Bioalliance Pharma, Paris, France (H.L., F.Z.)
Styrylquinoline derivatives (SQ) efficiently inhibit the 3'-processing activity of integrase (IN) with IC50 values of between 0.5 and 5 µM. We studied the mechanism of action of these compounds in vitro. First, we used steady-state fluorescence anisotropy to assay the effects of the SQ derivatives on the formation of IN-viral DNA complexes independently of the catalytic process. The IC50 values obtained in activity and DNA-binding tests were similar, suggesting that the inhibition of 3'-processing can be fully explained by the prevention of IN-DNA recognition. SQ compounds act in a competitive manner, with Ki values of between 400 and 900 nM. In contrast, SQs did not inhibit 3'-processing when IN-DNA complexes were preassembled. Computational docking followed or not by molecular dynamics using the catalytic core of HIV-1 IN suggested a competitive inhibition mechanism, which is consistent with our previous data obtained with the corresponding Rous sarcoma virus domain. Second, we used preassembled IN-preprocessed DNA complexes to assay the potency of SQs against the strand transfer reaction, independently of 3'-processing. Inhibition occurred even if the efficiency was decreased by about 5- to 10-fold. Our results suggest that two inhibitor-binding modes exist: the first one prevents the binding of the viral DNA and then the two subsequent reactions (i.e., 3'-processing and strand transfer), whereas the second one prevents the binding of target DNA, thus inhibiting strand transfer. SQ derivatives have a higher affinity for the first site, in contrast to that observed for the diketo acids, which preferentially bind to the second one.
Address correspondence to: Jean-François Mouscadet, UMR CNRS-8113, Laboratoire de Biotechnologies et Pharmacologie Génétique Appliquée (L.B.P.A.), Ecole Normale Supérieure de Cachan, 61 avenue du Président Wilson, 94235 Cachan Cedex, France. E-mail: mouscadet{at}lbpa.ens-cachan.fr
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