Explore the function of Insulin-Degrading-Enzyme (IDE) with small chemical modulating Ligands.
The objective of the project is to study the role of insulin-degrading enzyme (IDE) in cells and in normal and sick mice using small exosite modulators of IDE that modify the substrate binding pocket occupancy and the proteolytic profile of IDE. The project focuses on Type-II-diabetes and Alzheimer’s disease, two diseases where insulin and β-amyloid peptide, two cognate substrates of IDE, are involved. The data produced by the project will allow a better understanding of the (patho)-physiological role of IDE. The discovered modulators could eventually find applications in these pathologies. This project is tailored within the framework of 4 complementary teams: Medicinal chemistry / Chemical biology / ADME-PK (Déprez et al), Protein expression, crystallization and X-ray structure determination (Tang et al), Cell biology and vivo (van Endert et al) and Diabetes (Staels et al).
Deprez’s team has a strong experience in the screening and optimization of modulators of Zinc-metalloproteases. In the course of the screening of a proprietary 2500-compound library on IDE using a labeled Aβ substrate, we identified a 5 µM inhibitor. The co-crystal structures revealed that very interestingly, our compounds bind to the exosite of IDE. Consistent with that observation, in vitro modulation of IDE in the presence of our compounds is variable depending on the substrate. Our compounds behave as either inhibitors or activators depending on the substrate. We also applied the concept of in situ Click-chemistry to IDE and obtained and optimized original inhibitors of this enzyme. Compounds have shown activity in vivo.
Deprez-Poulain, R., et al Catalytic site inhibition of IDE induces glucose intolerance in mice. Nature Comm., 2015, 6. doi:10.1038/ncomms9250 OPEN ACCESS
Deprez-Poulain, R. From In situ Click to in vivo pharmacology: Effect of catalytic site inhibition of Insulin Degrading Enzyme on glucose tolerance,51st International Conference on Medicinal Chemistry,Avignon, France,1st-3rd July 2015, Invited.