Targeting GPR35 for the treatment of IBD
➜ GPR35: an emerging therapeutic target
The G protein-coupled receptor 35 (GPR35) is an orphan receptor identified nearly three decades ago. It is uniquely expressed in the gastrointestinal tract and within various immune cells. Recently, GPR35 has emerged as a crucial therapeutic target for Inflammatory Bowel Diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD). This association is supported by strong genetic evidence: single nucleotide polymorphisms within the GPR35 locus, such as the T108M mutation, are now recognized as major risk factors for UC.
➜ A multidisciplinary in silico/in vitro approach
The true strength of this project lies in its inherently multidisciplinary nature. To address this complex challenge, we combine cutting-edge computational approaches (in silico) with experimental cell biology models (in vitro).
This synergy allows us to explore molecular interactions at the atomic level and rationalize drug candidate discovery via virtual screening, before rigorously validating their activity and functional profile (signaling bias) within our biological models.
➜ The dual role of the GPR35 receptor
The involvement of this receptor in IBD is highly complex and characterized by a dual function:
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Pro-inflammatory action: Activation of the Gα12/13 and Gi/o protein pathways generally promotes inflammation.
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Anti-inflammatory action: Conversely, β-arrestin-2 recruitment is associated with protective responses.
Furthermore, GPR35 exhibits significant constitutive activity (independent of the presence of an agonist), which plays an essential role in maintaining the integrity of the colonic epithelial barrier. Studies have demonstrated that inhibiting this basal activity with inverse agonists significantly increases mucosal barrier permeability. This indicates that only agonists possess genuine therapeutic potential for tissue repair.
Despite its clear clinical potential, defining the pharmacology of GPR35 remains a major challenge. Proposed endogenous ligands, such as kynurenic acid, exhibit very low potency at the human receptor, while synthetic reference compounds (such as lodoxamide) lack pathway selectivity.
➜ Our objectives: atomic-level pharmacology and biased signaling
Our primary objective is to overcome these pharmacological limitations through the elucidation of GPR35 pharmacology at the atomic level and the identification of new, highly selective agonists, ideally possessing a signaling profile functionally biased toward different biological response cascades.
By specifically favoring the protective β-arrestin-2 pathway over the pro-inflammatory Gα pathways, our ambition is to exploit GPR35’s mucosal healing properties while minimizing immune-mediated inflammation.
➜ Our group
Principal investigator of GPR35 project