P2X7

The P2X purinergic receptor 7 (P2X7) is a poorly selective ATP-gated ion channel, expressed in many cell types, including immune cells (macrophages and microglia) and cells in the central and peripheral nervous systems. P2X7 has low affinity for extracellular ATP (mM range) and is activated in the presence of high levels of extracellular ATP as a result of inflammation or cell damage. P2X7 signalling affects major cell functions and cell fate, including inflammation, proliferation, metabolism and cell death. P2X7 is implicated in both physiological and pathophysiological processes such as inflammation, innate immunity, tumour progression, neurodegenerative disease, and several other diseases.

Functional P2X7 is formed by a complex of three monomers of 595 amino acids. Each monomer is composed of a short cytoplasmic N-terminal domain, an extracellular domain bearing the ATP binding site, two transmembrane helices, and a long C-terminal cytoplasmic domain. Upon ATP binding, the trimeric complex becomes rapidly permeable to cations, leading to Ca²⁺ and Na⁺ influx, and efflux of K⁺. Sustained exposure to ATP induces the formation of a poorly selective membrane pore, termed the large pore, that allows the uptake of molecules of up to 900 Da in weight. These plasma membrane events induce downstream intracellular signalling pathways that regulate different cellular functions, such as activation of the inflammasome, ROS production, regulation of metabolism, cytokine maturation and release leading to inflammation or cell proliferation. Therefore, P2X7 presents as an emerging therapeutic target in the treatment of infectious and inflammatory diseases, neuropathic pain and cancers.

Our group is interested in developing both negative and positive P2RX7 modulators, by medicinal chemistry programs. Indeed, some of our compounds were negative allosteric modulators of P2X7 and efficient in mouse models of Inflammatory Bowel Diseases (Homerin et al., J Med Chem 2019). We also developed and patented a positive modulator, named HEI3090. This compound was effective against lung cancer by promoting anti-tumoral immune responses (Douguet et al., Nat Comm 2020) and against pulmonary fibrosis (Janho dit Reich, eLife 2023).

Our studies aim at developing new P2X7 modulators, studying their biological activities and identifiying the molecular mechanisms regulating pore opening by advanced pharmacological studies of the allosteric modulators binding onto wild-type and mutated P2X7 as well as computational molecular dynamic simulations explaining our experimental observations (https://doi.org/10.1021/acsptsci.4c00582).