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Séminaire - Mario Van der StelltA Chemical Biology Approach to Control Endocannabinoid Biosynthesis

Abstract :

 Endocannabinoids play an essential role in human health and disease, regulating processes such as immunomodulation, energy balance and neurotransmission.
Diacylglycerollipase-α (DAGL-α) is responsible for the production of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the central nervous system. It is a potential drug target for the treatment of obesity and neurodegenerative diseases. Currently, there are no selective inhibitors and activity-based probes available for its study.
The identification of selective DAGL-a inhibitors is hampered by a lack of assays that make use of endogenous DAGL-a activity in proteomes. Determination of the selectivity of the inhibitors in native tissues is important, because DAGL-a belongs to the class of serine hydrolases, containing more than 200 members with various physiological functions.

Here, I will present a chemical biology approach to identify and characterize highly selective chemical probes to study the function of this protein both in vitro and in vivo.

Selected publications

Baggelaar et al. Angewandte Chemie Int. Ed. Eng., 2013, doi: 10.1002/anie.201306295.

van der Stelt, M., J. Cals, S. Broeders-Josten, J. Cottney, A.A. van der Doelen, M. Hermkens, V. de Kimpe, A. King, et al., "Discovery and Optimization of 1-(4-(Pyridin-2-yl)benzyl)imidazolidine-2,4-dione Derivatives As a Novel Class of Selective Cannabinoid CB2 Receptor Agonists", Journal of Medicinal Chemistry, vol. 54, no. 20, pp. 7350-7362, Oct 27, 2011. DOI: 10.1021/Jm200916p

van der Stelt, M., M. Trevisani, V. Vellani, L. De Petrocellis, A.S. Moriello, B. Campi, P. McNaughton, P. Geppetti, et al., "Anandamide acts as an intracellular messenger amplifying Ca2+ influx via TRPV1 channels", Embo Journal, vol. 24, no. 17, pp. 3026-3037, Sep 7, 2005. DOI: 10.1038/Sj.Emboj.7600784

Scientific focus :

In a multidisciplinary research line, in which organic and medicinal chemistry are combined with molecular biology and chemical biology, we aim to a) develop assays to determine the activity of proteins, and b) to design, synthesize and characterize small molecules that act as chemical tools to visualize and control protein activity. We use computational chemistry together with activity-based probes for compound profiling and optimization. In (inter)national collaborations with biologists and pharmacologists we test our molecules in preclinical models of disease. Our current projects focus on kinases and proteins of the endocannabinoid system.