The TGR5 receptor is a G-protein coupled membrane receptor (GPCR) whose natural ligands are bile acids. TGR5, whose activation in the gut stimulates GLP-1 secretion, is described as a potential target for metabolic diseases. TGR5 activation has also been shown to decrease the production of pro-inflammatory cytokines in various tissues and organs. In this project, we have developed a potent TGR5 agonist with targeted distribution in the gut that is currently being evaluated in mouse models of metabolic (NASH, diabetes) and inflammatory (IBD).
Former members : Rajaa Boulahjar PhD - Post-doc; Manuel Lasalle - PhD student; Vanessa Hoguet - PostDoc; Helene Gras-Masse Pr - PhD - PharmD
This project is a multidisciplinary project in collaboration with the teams of Bart Staels (U1011), Jürgen Siepmann (U1008) and Philippe Chavatte (EA4481) which integrates all the aspects of drug discovery (screening, molecular modeling, cell and animal biology, pharmacokinetic and industrial property). A library of 20.000 compounds has been screened on the receptor and allowed the identification of hits from diverse chemical series. 5 chemicals series have been selected for further optimization. The conception of analogs will be assisted by molecular modelling. A pharmacophoric model is being validated and will allow the in silico screening of compound generated in the lab by the software Pipeline PilotTM.
Three TGR5 agonists of the literature have been synthesized and allow the calibration of the secondary assays and in vivo tests by the biologists of the project. More than 50 analogs have been synthesized and tested on both murine and human TGR5 receptor. First results allowed to understand the structure-activity relationships. We are now working in parallel on 3 chemicals series.
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