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Accueil > Teams > Pharmacognosy - Chemistry of Natural Products > NICOFIVE Discovery of allosteric modulators specifically targeting α5-containing nAChRs

NICOFIVE Discovery of allosteric modulators specifically targeting α5-containing nAChRs

The team of “Chimie des Substances Naturelles » (D. Joseph) is one partner of the PRC ANR project untitled NICOFIVE which associates two additional partners of the Pasteur Institute of Paris, the unit “Récepteurs-Canaux” (P.-J. Corringer, coordinator) and the unit “Bio-informatique Structurale” (A. Blondel). The objective is to discover specific ligands of the accessory nAChR α5-subunit. Acting as positive allosteric modulators, these ligands would have direct clinical applications for the treatment of smoking dependence and lung cancer. Based on a mutated AChBP model protein and already identified alkaloid "hits", this project implements an innovative strategy of de novo discovery of PAMα5. It combines fragment-based approaches and kinetic target-guided synthesis to in silico docking, SPR-binding and X-ray crystallography assays. We thus propose an integrated approach, combining biochemical, electrophysiological and structural experiments with in silico modelling, organic chemistry and chemical biology, to achieve the challenge of rationally developing a novel class of PAMα5.