Small molecules as therapeutic options in Parkinson’s disease: case of modulators of UCH-L1 and GLP-1 receptor

Joint PhD at UNamur and Abaxys Therapeutics

Candidate

Kalina MAMBOURG

Promoters

Prof. Johan WOUTERS, UNamur, Department of chemistry, Laboratory of structural biological chemistry (CBS) 

Jury

• Dr Catherine MICHAUX (département de chimie, UNamur), présidente
• Prof. Johan WOUTERS (département de chimie, UNamur), secrétaire
• Prof. Steve LANNERS (département de chimie, UNamur)
• Dr Javier GARCIA-LADONA (Abaxys Therapeutics SA)
• Prof. Tom LEYSSENS (Institute of Condensed Matter and Nanosciences, Université catholique de Louvain)

Summary

Parkinson’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 protein. 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 :  

(i) Synthesize and formulate a derivative of 1,2,4-oxadiazole, an agonist of GLP-1R, as a co-amorphous system with saccharin or citric acid.

(ii) Investigate alanylpiperidine derivative compounds as activators of UCH-L1 in silico and in vitro. The salification of these compounds was then studied in order to increase their solubilities.

(iii) Characterize in silico et in vitro an ortholog of UCH-L1 human protein, UCH-L1 zebrafish, and to study the behavior of these proteins towards similar ligands.