Conception et synthèse d’agonistes topiques intestinaux du récepteur aux acides biliaires
TGR5 : contrôle de l’engagement de la cible par des modifications chimiques innovantes
Topical Intestinal Agonists of the Bile Acid Receptor TGR5 : Controlling Target Engagement
by Innovative Molecular Engineering
Julie Charton, PhD, MCU, INSERM U1177 Drugs and Molecules for Living Systems – Université de Lille – Institut Pasteur de Lille
TGR5 is a ubiquitous GPCR sensitive to bile acids. It is mostly expressed in the liver, the gallbladder,
the nervous system, some immune cells, and in the intestine where it is expressed at the membrane
of enteroendocrine L cells. Activation of TGR5 in these cells increases the secretion of GLP-1, an
incretin hormone implicated in glucose and energy homeostasis. Therefore, pharmacological
targeting of TGR5 may constitute a promising incretin-based strategy for the treatment of type 2
diabetes and associated metabolic disorders. Nevertheless, recent experiments have also shown that
activation of TGR5 by systemic agonists in mouse models could induce unwanted effects.
We have hypothesized that a selective activation of TGR5 limited to the intestine without systemic
exposure would be powerful enough to obtain beneficial effect on glucose homeostasis via GLP-1
secretion, while preventing potential adverse effects.
To prevent systemic exposure and generate compounds with restricted action in intestine, we
performed an innovative molecular engineering of our TGR5 agonists. Using the structure-activity
relationships obtained in the series, we introduced, on a mute position, some structural elements
called kinetophores. Such modified analogs, exhibiting low permeability while keeping nanomolar
potencies on TGR5, are able to reach the desired tissue, the distal intestine, with high concentrations
allowing a potent target engagement. Some of these compounds have been evaluated in vivo in mice
and triggered potent GLP-1 secretion. The design, synthesis and characterization issues of such
compounds as well as their pharmacological and ADME evaluation, in vitro and in vivo will be
presented.
Julie Charton graduated as an engineer in chemistry in 2001 from the Ecole Nationale Superieure de
Chimie de Lille (ENSCL). After her PhD on medicinal chemistry in 2004 under the supervision of Pr
Sergheraert (UMR8525, Institut de Biologie de Lille), she worked, as a postdoctoral researcher, on
the conception and synthesis of ligands of zinc metalloproteases in Pr Benoit Deprez’ laboratory.
Since 2007, she is assistant professor in organic chemistry at the Faculty of Pharmacy of Lille. Her
research at INSERM U1177 “Drugs and Molecules for Living Systems” (INSERM, Pasteur Institute,
University of Lille) focused on the development of intestine-targeted agonists of the bile acids
receptor TGR5 by innovative chemical engineering. Since 2020, she works on a project aiming at
identifying pan-inhibitors of the 3CL protease, an essential component of the replication cycle of
coronaviruses, to develop broad spectrum antiviral agent against SARS-CoV-2 and potential
emergent coronaviruses.