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Targeting P2RX7 to control intestinal epithelial cell homeostasis and colonic inflammation

Mucosal epithelial cells represent an efficient and crucial first-line defense barrier positioned at the interface between the inner and the outer part of the body. Activation of epithelial cells by pathogens or by the normal microbiota results in host defense responses that include the production of pro-inflammatory cytokines and recruitment of mucosal immune cells. Conversely, factors produced by immune cells can regulate function and proliferation of intestinal epithelial cells and affect barrier integrity. Chronic inflammatory bowel diseases (IBD) are thought to arise from an inappropriate immune response that can be exacerbated by a perturbation of the barrier integrity. Extracellular ATP (eATP) acting on the purinergic P2RX7 receptor has recently emerged as a key signaling pathway in the control of cytokines production, regulatory T cells (Tregs) function, mast cell dependent intestinal inflammation, and death of enteric neurons during colitis. Despite important efforts to develop drugs inhibiting the multifaceted P2RX7 by leading pharmacological industries, very few studies have so far analyzed the global in vivo effect of its modulation on gut healing during colitis.

Our consortium, has already demonstrated that P2RX7 is differentially expressed in the mucosa of patients with active and quiescent IBD and uncovered that P2RX7 signaling positively regulates the inflammatory response and negatively regulates Tregs functions. We recently demonstrated using the classical P2RX7-/- mice treated with DSS that P2RX7-dependent signaling promotes, as expected, intestinal inflammation. Indeed, all indicators of colitis severity (survival, loss of body weight, and reduction of colon length) were significantly ameliorated in P2RX7‑/- mice challenged with DSS. Importantly, these results were reproduced using two commercially available chemical compounds antagonizing P2RX7, namely A438079 and A740003 compounds. The aim of this work is to develop novel small-molecules P2RX7-specific antagonists.  We have initiated a “ligand-based” approach to define a novel pharmacophore based on the extensive computational comparison of known P2RX7 antagonists.

One hundred compounds corresponding to this pharmacophore have been synthesized so far and screened in vitro. Not surprisingly, novel antagonists of human P2RX7, representing new promising “hits” for drugs development, have been identified during this first round of screening (e.g., compounds HEI2257 and ALIPX49). The main objective of this part of the project is to develop news chemical analogs based on our first hits, to enhance their pharmacological activities, to synthesize new heterocyclic scaffolds corresponding to their rigidified analogs, to screen their activity in vitro using already developed methods implemented and, finally to evaluate their therapeutic potential in vivo.


1. Baudelet D, Lipka E, Millet R, Ghinet A. Involvement of the P2X7 purinergic receptor in inflammation: an update of antagonists series since 2009 and their promising therapeutic potential. Curr Med Chem. 2015;22(6):713-29.


2. Baudelet D, Furman C, Ghinet A, Dezitter X, Adriouch S, Capet F, Rogez-Florent T, Gautret P, Rigo B, Millet R, Vaccher C, Lipka E. Evaluation and comparison of three different separation techniques for analysis of retroamide enantiomers and their biological evaluation against h-P2X7 receptor. J Chromatogr B Analyt Technol Biomed Life Sci. 2015 Apr 1;986-987:35-43. doi: 10.1016/j.jchromb.2015.02.001.


3.  Baudelet D, Schifano-Faux N, Ghinet A, Dezitter X, Barbotin F, Gautret P, Rigo B, Chavatte P, Millet R, Furman C, Vaccher C, Lipka E. Enantioseparation of pyroglutamide derivatives on polysaccharide based chiral stationary phases by high-performance liquid chromatography and supercritical fluid chromatography: a comparative study. J Chromatogr A. 2014 Oct 10;1363:257-69. doi: 10.1016/j.chroma.2014.06.090.


4.  Baudelet D, Ghinet A, Furman C, Dezitter X, Gautret P, Rigo B, Millet R, Vaccher C, Lipka E. Antagonists of the P2X7 receptor: mechanism of enantioselective recognition using highly sulfated and sulfobutylether cyclodextrins by capillary electrokinetic chromatography. Electrophoresis. 2014 Oct;35(19):2892-9. doi: 10.1002/elps.201400113.