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Molecular Pharmacology

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Research ArticleArticle

Mechanism of HIV-1 Integrase Inhibition by Styrylquinoline Derivatives in Vitro

Eric Deprez, Sophie Barbe, Macieij Kolaski, Hervé Leh, Fatima Zouhiri, Christian Auclair, Jean-Claude Brochon, Marc Le Bret and Jean-François Mouscadet
Molecular Pharmacology January 2004, 65 (1) 85-98; DOI: https://doi.org/10.1124/mol.65.1.85
Eric Deprez
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Sophie Barbe
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Macieij Kolaski
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Hervé Leh
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Fatima Zouhiri
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Christian Auclair
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Jean-Claude Brochon
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Marc Le Bret
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Jean-François Mouscadet
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Abstract

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.

  • Received July 3, 2003.
  • Accepted October 10, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 65 (1)
Molecular Pharmacology
Vol. 65, Issue 1
1 Jan 2004
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Research ArticleArticle

Mechanism of HIV-1 Integrase Inhibition by Styrylquinoline Derivatives in Vitro

Eric Deprez, Sophie Barbe, Macieij Kolaski, Hervé Leh, Fatima Zouhiri, Christian Auclair, Jean-Claude Brochon, Marc Le Bret and Jean-François Mouscadet
Molecular Pharmacology January 1, 2004, 65 (1) 85-98; DOI: https://doi.org/10.1124/mol.65.1.85

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Research ArticleArticle

Mechanism of HIV-1 Integrase Inhibition by Styrylquinoline Derivatives in Vitro

Eric Deprez, Sophie Barbe, Macieij Kolaski, Hervé Leh, Fatima Zouhiri, Christian Auclair, Jean-Claude Brochon, Marc Le Bret and Jean-François Mouscadet
Molecular Pharmacology January 1, 2004, 65 (1) 85-98; DOI: https://doi.org/10.1124/mol.65.1.85
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