Analyse et modélisation de nouveaux inhibiteurs non nucléosidiques de la transcriptase inverse du virus de l'immunodéficience humaine de type 1 (VIH-1)

Abstract

Human Immunodeficiency Virus (HIV) is the causative agent of Acquired Immune DeficiencySyndrome (AIDS). Treatment of HIV-infected patients is currently based on the use of chemicalcompounds that interfere with various steps of the viral replication cycle (chemotherapy).Although these therapies allow for a significant improvement of a patient's health, theynonetheless remain imperfect and expensive. Research for new and improved anti-HIVcompounds is therefore necessary. This Ph. D. thesis is dedicated to the rational design and analysis of new non nucleosideinhibirors of HIV-1 reverse transcriptase (NNRTI), a key enzyme in HIV lifecycle. Most of thestudied compounds are derived from the 2-pyridinone ring, that is part of several NNRTIfamilies. Rational drug design usually requires a good understanding of the main interactions betweenthe macromolecular target (RT) and its ligands. However, no crystal structure of a RT-pyridinone complex has been reported yet. Our first objective was therefore to build atheoretical model describing RT-pyridinone interactions and providing a better understanding ofstructure-activity relationships among pyridinones. The information obtained in this theoreticalmodel was then used in order to develop new and potent inhibitors.

Date of Award	27 Feb 2004
Original language	French
Awarding Institution	University of Namur
Supervisor	Francois DURANT (Supervisor), Jean-Marie ANDRE (Jury), Laszlo HEVESI (Jury), Johan Wouters (Jury) & Arsène Burny (Jury)