TGR5 modulators

Team

  • Team Leader: Julie Charton PhD - Assistant Pr
  • Rajaa Boulahjar PhD - Post-doc
  • Manuel Lassalle - PhD student
  • Vanessa Hoguet - PostDoc
  • Helene Gras-Masse Pr - PhD - PharmD

Mission

The goal of the project is the discovery of ligands of the receptor TGR5 as pharmacological tools and potential therapeutic agents for the treatment of diseases linked to cholesterol and bile acid metabolism and homeostasis.

Approach

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.

Latest results

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.

Conferences

2018

  • Charton, J. Topical Intestinal Agonists of the Bile Acid Receptor TGR5: Controlling Target Engagement by Innovative Molecular Engineering,54th RICT-ICMC Interfacing Chemical Biology and Drug Discovery,Strasbourg, France,4th-6th Jul. 2018 Invited.

2016

  • Hoguet, V. Pharmacokinetic study of topical intestinal compounds,23rd Young Research Fellow Meeting of the SCT,15th-17th Feb. 2016, Flash presentation.

2015

  • Lasalle, M. Optimization and development of novel topical intestinal agonists of the bile acid receptor TGR5 for treatment of diabetes mellitus and associated metabolic diseases.,Cambridge, UK,16th-18th Sept. 2015, Flash communication.
  • Lasalle, M., Tailleux, A., Hennuyer, N., Dubanchet, B., Belloy, L., Leroux, F., Staels, B., Gras-Masse, H., Deprez, B., & Charton, J. Design of agonists of the bile acid receptor TGR5,22nd YRFM of the SCT,Biocitech, Romainville, France,4th-6th Feb 2015. 
  • Lasalle, M. Optimization and development of novel agonists of the bile acid receptor TGR5 for treatment of diabetes mellitus and associated metabolic diseases,2nd F3 Meeting,Ghent, Belgium,24th Mar 2015.

Poster communications

2019

  • Maingot, M., Hoguet, V., Lasalle, M., Piveteau, C., Leroux, F., Herledan, A., Biela, A., Sevin, E., Culot, M., Gosselet, F., Staels, B., Tailleux, A., Deprez, B., & Charton, J. Pharmacokinetic study of Pegylated TGR5 agonists 26th SCT Young Research Fellow Meeting, Paris, France, 20th-22nd Feb.,2019.

2017

  • Hoguet, V., Lasalle, M., Tailleux, A., Hennuyer, N., Belloy, L., Leroux, F., Piveteau, C., Staels, B., Deprez, B., & Charton, J. Development of new topical intestinal agonists of the bile acid receptor TGR5 for the treatment of type 2 diabetes. 24th Young Research Fellow Meeting of the SCT, Châtenay Malabry, France, 8th-10th February,2017.

2016

  • Hoguet, V., Lasalle, M., Piveteau, C., Leroux, F., Herledan, A., Biela, A., Belloy, L., Hennuyer, N., Boulahjar, R., Sevin, E., Culot, M., Gosselet, F., Staels, B., Tailleux, A., Deprez, B., & Charton, J. Pharmacokinetic study of topical intestinal compounds 23rd Young Research Fellow Meeting, SCT, Lille, France, 15th-17th Feb.,2016.
  • Boulahjar, R., Belloy, L., Picon, S., Hoguet, V., Hennuyer, N., Lasalle, M., Leroux, F., Piveteau, C., Sevin, E., Culot, M., Gosselet, F., Staels, B., Deprez, B., Tailleux, A., & Charton, J. Discovery and Structure-Activity Relationships of a new class of agonists of the bile acid receptor TGR5. 23rd Young Research Fellow Meeting of SCT, Lille, France, 15th-17th Feb.,2016.

2015

  • Lasalle, M., Tailleux, A., Hennuyer, N., Belloy, L., Piveteau, C., Herledan, A., Hoguet, V., Leroux, F., Gras-Masse, H., Staels, B., Deprez, B., & Charton, J. Optimization and development of novel topical intestinal agonists of the bile acid receptor TGR5 for treatment of diabetes mellitus and associated metabolic diseases. 18th SCI/RSC Symposium on Medicinal Chemistry., Cambridge UK, 13rd-16th Sept.,2015.

Prizes and Awards

2017

  • Hoguet, V. Best Poster presentation. Development of new topical intestinal agonists of the bile acid receptor TGR5 for the treatment of type 2 diabetes.

Articles

2018

  • Hoguet, V., Charton, J., Hecquet, P.-E., Lakhmi, C., & Lipka, E. Supercritical fluid chromatography versus high performance liquid chromatography for enantiomeric and diastereoisomeric separations on coated polysaccharides-based stationary phases: Application to dihydropyridone derivatives. J. Chromatogr. A,2018, 1549: 39-50.10.1016/j.chroma.2018.03.035

2017

  • Lasalle, M., Hoguet, V., Hennuyer, N., Leroux, F., Piveteau, C., Belloy, L., Lestavel, S., Vallez, E., Dorchies, E., Duplan, I., Sevin, E., Culot, M., Gosselet, F., Boulahjar, R., Herledan, A., Staels, B., Deprez, B., Tailleux, A., & Charton, J. Topical Intestinal Aminoimidazole Agonists of G-Protein-Coupled Bile Acid Receptor 1 Promote Glucagon Like Peptide-1 Secretion and Improve Glucose Tolerance. Journal of Medicinal Chemistry,2017, 60(10): 4185-4211. 10.1021/acs.jmedchem.6b01873
  • Delplanques, T., Boulahjar, R., Charton, J., Houze, C., Howsam, M., Servais, A.-C., Fillet, M., & Lipka, E. Single and dual cyclodextrins systems for the enantiomeric and diastereoisomeric separations of structurally related dihydropyridone analogues. Electrophoresis,2017, 38(15): 1922-1931.10.1002/elps.201600536
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