RésuméRecent researchs have highlighted the deregulation of enzyme levels for human
indoleamine-2,3-dioxygenase 1 (hIDO1) and 2 (hIDO2) in high mortality pathologies such as cancer or Covid-19. As a result, hIDO1 has been intensively studied in the scientific community, with interest particularly directed towards drug design. However, in 2019, one of the most promising drugs failed in the clinical phase, challenging the knowledge about the protein. Conversely, hIDO2 is only minimally characterized in the literature. Few inhibitors have been developed for this target. Improving the understanding of these two enzymes is crucial to help design new drugs.
One of the most overlooked issues for hIDO1 and hIDO2 is the plasticity of both
proteins. Recent research has highlighted the plasticity of the active site of hIDO1 and its potential involvement in activity. At present, the molecular bases associated to this plasticity remain unknown and the existence of such a mechanism in hIDO2 has not yet been proven. In this context, this work focuses on the structural and functional characterization of the proteins and the understanding of their plasticity. First, the two enzymes were characterized according to their physicochemical properties in order to compare them. Secondly, a multidisciplinary structural study, involving crystallography as well as Molecular Dynamics, has been performed on each target, in order to deepen the structural knowledge. Finally, with this new information, a model to explain the plasticity of each protein and the interactions between the two systems was proposed. Together, all these results improve the understanding of the two enzymes and form a solid basis for the development of new potential therapeutic
|la date de réponse
|16 nov. 2022
|Johan Wouters (Promoteur), Yoann Olivier (Président), Laurence Leherte (Jury), Geoffray Labar (Jury), Ute F. Röhrig (Jury) & René Wintjens (Jury)