Leader: Xavier Dezitter
Workpackage: WP4
Purinoceptor P2X7, encoded by P2RX7 gene in humans, is a receptor of ATP whose binding leads to inflammation or apoptosis. Activation of the channel by ATP leads to cell depolarization from Ca2+ or Mg2+ transfer activating a pathway up to the transcription of pro-inflammatory genes within immune cells whereas saturating and continued concentrations of ATP increase consistently cell permeability leading to apoptosis.
That is why P2X7 receptors are promising therapeutic targets for treatment of inflammation and cancer. In this context, our scientists have developed P2X7 antagonists, in a first time, in order to decrease cation transfer and further inflammtion mediated by this receptor (10.1021/acs.jmedchem.9b00584). Then, more recently, they have developed unique molecules displaying anti-tumor properties in a mice model (10.1038/s41467-021-20912-2). Actually our studies aim at identifiying more powerful P2X7 modulators from study of molecular mechanisms accompanying pore opening by advanced pharmacological studies of the known allosteric modulators onto P2X7 wild and mutants as well as computational molecular dynamic simulations explaining these experimental observations.