Structural study of HIV-1 integrase inhibition by quinolones: contribution to the rational design of new inhibitors

  • Pierre Vandurm

Student thesis: Doc typesDoctor of Sciences


In the design of new antiviral agents against AIDS, HIV-1 integrase is an attractive target because this enzyme plays an essential role in the virus replication cycle by integrating the viral DNA into the host cell genome. Among all integrase inhibitors described to date, the β-diketo acid derivatives represent an important family. These compounds have the particularity to posess a chemical group able to chelate the Mg2+ metal cofactor present in the enzyme active site and essential to its catalytic activity. In this thesis, we have undertaken the study of the mechanism of inhibition of HIV-1 integrase by substituted quinolone based on experimental and theoretical approach. A series of quinolone substituted at position 3 by a β-diketo-acide/ester motif able to chelate the Mg2+ metal cofactor and at position 6 by various groups (halogen, hydrophilic or hydrophobic groups) has been synthesized as potential HIV-1 integrase inhibitors. These compounds were evaluated for their anti-integrase activity in in vitro assays using integrase overexpressed in E. coli and purified by affinity chromatography. The antiviral activity of compounds was also tested in ex vivo assays. To obtain the three-dimensional structure of an enzyme-ligand complex, the catalytic core domain of HIV-1 integrase was overexpressed in E. coli and purified by affinity chromatography. To improve the level of purity of the active protein obtained, other purification techniques were tested. Experimental studies (XRD, UV-visible, FT-IR, ATR) and theoretical calculations on the diketo acid compounds allowed to identify the most stable conformations of the diketoacid moiety and its complexation mode in solution with the Mg2+ cofactor. To determine the binding mode of developed quinolone within the DNA-bound enzyme, integrase/DNA model was built. Docking studies highlighted a binding mode in agreement with the observed structure-activity relationships. These molecular modeling studies allowed us to propose a mechanism of inhibition of HIV-1 integrase by quinolone compounds.
Date of Award3 Oct 2011
Original languageEnglish
Awarding Institution
  • University of Namur
SupervisorJohan Wouters (Supervisor), BERNARD MASEREEL (Jury), Xavier De Bolle (Jury), Davide BONIFAZI (President) & Jean-François Mouscadet (Jury)

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