TGR5 modulators

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).

Team

  • Team Leader: Julie Charton PhD - Assistant Pr
  • Florence Leroux, PhD, PharmD
  • Catherine Piveteau
  • Alexandre Biela

Former members : Rajaa Boulahjar PhD - Post-doc; Manuel Lasalle - PhD student; Vanessa Hoguet - PostDoc; Helene Gras-Masse Pr - PhD - PharmD

Collaborators

  • Pr Anne Tailleux

Grants

Approach

This project is a multidisciplinary project in collaboration with the teams of Bart Staels (U1011), JŘrgen 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.

Publications

2021

  • Hoguet, V., Lasalle, M., Maingot, M., Dequirez, G., Boulahjar, R., Leroux, F., Piveteau, C., Herledan, A., Biela, A., Dumont, J., Chávez-Talavera, O., Belloy, L., Duplan, I., Hennuyer, N., Butruille, L., Lestavel, S., Sevin, E., Culot, M., Gosselet, F., Staels, B., Deprez, B., Tailleux, A., & Charton, J. Beyond the Rule of 5: Impact of PEGylation with Various Polymer Sizes on Pharmacokinetic Properties, Structure–Properties Relationships of mPEGylated Small Agonists of TGR5 Receptor. Journal of Medicinal Chemistry,2021.10.1021/acs.jmedchem.0c01774

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

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

  • 24th YRFM of the SCT, Best Poster presentation.  to Hoguet, V., (Feb 2017), Development of new topical intestinal agonists of the bile acid receptor TGR5 for the treatment of type 2 diabetes, Châtenay-Malabry, France,
  • 1st Forum Recherche.Best Poster Prize.   to Hoguet, V. (Jul 2017) Development of new topical intestinal agonists of the bile acid receptor TGR5 for the treatment of type 2 diabetes, School of Pharmacy, Lille, France.
  • 24th YRFM of the SCT, Best Poster Communication to Hoguet, V. (Feb 2017) Development of new topical intestinal agonists of the bile acid receptor TGR5 for the treatment of type 2 diabetes, Châtenay-Malabry, France.

2015

  • 22nd YRFM of the SCT, Best Oral Communication, (Mar 2015) to Lasalle, M. Design of agonists of the bile acid receptor TGR5, Biocitech, Romainville, France.

2014

  • 14th Journées André Verbert (Sep 2014), Best oral communication to Lasalle, M., Lille France.
  • 1st of Regional Famelab Selection (Mar 2014) to Lasalle, M. Recepteurs intestinaux aux nutriments: interaction diabète et nutrition Villeneuve d'Ascq, France
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