Signaling bias

For many years, the team has studied how the binding of natural ligands to G protein-coupled receptors (GPCRs) leads to the production of intracellular second messengers, via their coupling with various antibody transducing molecules such as G proteins and beta-arrestins. Thanks to detailed pharmacological characterization, the team also identifies ligands that preferentially activate one of the transducing proteins, called biased ligands, or allosteric modulators that modify the activity of the receptor induced by the endogenous ligand. These ligands make it possible to identify which specific signaling networks are induced by the different transducing proteins. They are of great therapeutic interest because they make it possible to specifically control the activation of the receptor, while minimizing possible side effects.

To understand the complexity of the molecular networks induced by the activation of GPCRs, BIOS is inspired by the methodology of systems biology. Biochemical reaction networks are modeled as ordinary differential equations. This methodology involves medium-sized models (around ten variables, around twenty parameters) whose calibration requires good parametric inference capacity. Another challenge is to understand the behavior of these models in “long” time (compared to the time scales of biochemical reactions). This question is essential for systems biology, whose central hypothesis is that the dynamics of molecular interactions will dictate the cellular response to a stimulus. BIOS's project is to explore the use of the theory of biochemical reaction networks to describe possible stationary states given a given topology, as well as other methodological approaches such as Boolean networks or recurrent neural networks for
time series prediction.
At the experimental level, different ligands are tested in the BIOS team: glycoprotein hormones, peptides, and small chemical molecules. In addition, BIOS has been developing antibody fragments against FSHR, LHR and OTR for several years. The team recently constructed its own synthetic library of antibody fragments based on natural camelid immunological repertoires. Antibody fragments showing pharmacological properties of biased allosteric or orthosteric ligands have been identified. They are now being administered in vivo in mice (see #multi-scale). In addition, the team plans to use these antibody fragments to better understand the structure, activation mechanisms and signaling of these GPCRs, more particularly the intrabodies targeting the intracellular parts. The team's work on antibody fragments is part of LabEx MAbImprove, with which the BIOS team has been associated since 2011, as well as the Biomedicines dynamic of the Center Val-de-Loire region.

Fundings

1. Bill & Melinda Gates Foundation, Contrabody, Eric REITER (2021-2023, 1.8 M $ US), , 1 academic partner, 2 industrial partner, leader.
2. Région Centre Val de Loire, ARD2020 Biomédicaments Phase 3, SELMAT, Eric REITER (2020-2023, 630 K€), 3 academic partner, 1 industrial partner, leader.
3. ERC starting grant, Lucie PELLISSIER (2020-2025), New molecular targets and proof-of-concept therapies for Autism Spectrum Disorders (THERAUTISM).
4. Région Centre Val de Loire, APR IR, INTACT, Pascale CRÉPIEUX (2019-2022), MCSaF, leader.
5. ANR YDOBONAN, Vincent AUCAGNE (2021-2024) CBM CNRS Orléans, partner.
6. Région Centre Val de Loire, APR IR, NeuroMAbster, Séverine MORISSET-LOPEZ (2018-2022) CBM CNRS Orléans, INEM CNRS Orléans, partner.
7. Région Centre Val de Loire, APR IR, LIPICABS, Marie POTIER-CARTEREAU (2018-2022), N2C INSERM, Tours, Synthelis, partner.
8. LabEx MabImprove.

Team people involved:

Thésards : Caroline Gora, Juliette Gourdon
Postdocs : Camille Gauthier, Pauline Raynaud, Vinesh Jugnarain, Maya Haj-Hassan, Léo Darrigade
ITA CDD: Amandine Vallet, Lucile Drobecq
ITA : Thomas Boulo, Christophe Gauthier
Chercheurs : Pascale Crépieux, Lucie Pellissier, Anne Poupon, Véronique Bozon, Frédéric Jean-Alphonse, Gilles Bruneau, Eric Reiter, Yves Combarnous, Danièle Klett, Misbah Razzaq, Romain Yvinec, Nicolas Azzopardi

Communautés scientifiques: GDR Reproscience, IRN GPCRnet, LabEx MAbImprove, EPC Musca