Jean-François Mouscadet

Chemistry and Structure-Activity Relationship of the Styrylquinoline-Type HIV Integrase Inhibitors

In spite of significant progress in anti-HIV-1 therapy, current antiviral chemo-therapy still suffers from deleterious side effects and emerging drug resistance. Therefore, the development of novel antiviral drugs remains a crucial issue for the fight against AIDS. HIV-1 integrase is a key enzyme in the replication cycle of the retrovirus since it catalyzes the integration of the reverse transcribed viral DNA into the chromosomal DNA. Efforts to develop anti-integrase drugs started during the early nineties, culminating with the recent approval of Raltegravir. The discovery and the development of the styrylquinoline inhibitor class was an important step in the overall process. In this review we have described the key synthetic issues and the structure-activity relationship of this family of integrase inhibitors. Crystallographic and docking studies that shed light on their mechanism of action are also examined.

Investigation of Novel Lipid-Functionalized PNA Monomers as Potential HIV-1 Non-Nucleoside Reverse Transcriptase and/or Integrase Inhibitors

A range of novel N-terminal lipid-functionalized peptide nucleic acid (PNA) monomers have been prepared and their abilities to inhibit HIV-1 reverse transcriptase and integrase have been examined.

Biochemical properties of the xenotropic murine leukemia virus-related virus integrase

Xenotropic Murine Leukemia Virus-related Virus (XMRV) is a new gammaretrovirus generated by genetic recombination between two murine endogenous retroviruses, PreXMRV1 and PreXMRV2, during passaging of human prostate cancer xenografts in laboratory mice. XMRV is representative of an early founder virus that jumps species from mouse to human cell lines. Relatively little information is available concerning the XMRV integrase (IN), an enzyme that catalyzes a key stage in the retroviral cycle, and whose sequence is conserved among replication competent retroviruses emerging from recombination between the murine endogenous PreXMRV-1 and PreXMRV-2 genomes. Previous studies have shown that IN inhibitors efficiently block XMRV multiplication in cells. We thus aimed at characterizing the biochemical properties and sensitivity of the XMRV IN to the raltegravir, dolutegravir, 118-D-24 and elvitegravir inhibitors inxa0vitro. We report for the first time the purification and enzymatic characterization of recombinant XMRV IN. This IN, produced in Escherichia coli and purified under native conditions, is optimally active over a pH range of 7-8.5, in the presence of Mg(2+) (15xa0mM and 30xa0mM for 3-processing and strand transfer, respectively) and is poorly sensitive to the addition of dithiothreitol. Raltegravir was shown to be a very potent inhibitor (IC50xa0∼xa030xa0nM) whereas dolutegravir and elvitegravir were less effective (IC50xa0∼xa0230xa0nM and 650xa0nM, respectively). The 118-D-24 drug had no impact on XMRV IN activity. Interestingly, the substrate specificity of XMRV IN seems to be less marked compared to HIV-1 IN since XMRV IN is able to process various donor substrates that share little homology. Finally, our analysis revealed some original properties of the XMRV IN such as its relatively low sequence specificity.