RésuméParkinson’s disease (PD) is a chronic and progressive neurodegenerative disorder of the central nervous system inducing severe motor disturbance. The current available treatments are effective for relieving motor symptoms but they do not alter the progression of the disease. Subsequently, there is an urgent need to develop disease modifying therapies that address the neurodegenerative processes. During the present PhD thesis, we have been investigating: the deubiquitinase UCH-L1 and GLP-1 receptor (GLP-1R). UCH-L1 is involved in the ubiquitin-proteasome system modulating the integrity of cellular proteins. The GLP-1R promotes insulin secretion and has shown neuroprotective properties in PD models. Combining ligands with these proteins can impact the progression of PD. Therefore, the objective of this thesis is to study small molecules acting as ligands of UCH-L1 and GLP-1R, two protein targets that are involved in the development of PD.
The research conducted during this work allowed us to identify, synthesize and formulate a new agonist of GLP-1R as a co-amorphous system with saccharin or citric acid. Furthermore, an investigation of activators of UCH-L1 were conducted in silico and in vitro. The salification of these new compounds was then studied in order to increase their solubility. Finally, a characterization of zebrafish UCH-L1, an ortholog of human UCH-L1 protein, was conducted as to ensure that zebrafish is a potential good in vivo model to study UCH-L1 ligands.
|la date de réponse||31 mars 2022|
|Superviseur||Johan Wouters (Promoteur), Catherine Michaux (Président), Steve Lanners (Jury), Javier Garcia-Ladona (Jury) & Tom Leyssens (Jury)|