A fundamental ethical and societal issue concerning the Department of Neuroscience is the overall burden of brain pathologies, especially in the time of COVID-19. Therefore, it is an urgent responsibility to contribute to the discovery of new brain chemical therapeutics in parallel/complement to the immunological tools. The research of the Emeritus team is focused on the allosteric modulation of pentameric ligand-gated ion channels (pLGICs) and their relevance to COVID-19.
The concept of allosteric regulation contrasts with the classical mechanism of competitive ligands interaction for a common site as it takes place between topographically distinct sites coupled by a discrete and reversible conformational change of the protein. The concept applies to signal transduction at chemical synapses, which is mediated by membrane receptors for neurotransmitters such as the pentameric ligand-gated ion channels (pLGIC), which include the nicotinic acetylcholine receptor (nAChR), the GABA receptor (GABAR), or the glycine receptor (GlyR). These receptors are involved in fundamental cognitive processes such as attention, learning, and memory and contribute to health deficits as important as Alzheimer’s, schizophrenia, or pain. They are oligomeric transmembrane proteins that carry ligand-binding sites for allosteric modulators topologically distinct from the neurotransmitter binding sites and mediate the signal transduction process via reversible conformational transitions between resting, open channel, and desensitized states (Cecchini & Changeux 2021).
By capitalizing on the constantly developing structural information at high resolution, the aim is the design of allosteric modulators for nAChR and GlyR which are not only selective but also specific to their site on one conformation of the receptor over the others. This strategy, here termed state-based pharmacology (Cerdan et al 2020), should open to the rational design of modulators with a characteristic physiological action such as activators vs inhibitors vs desensitizers. Compounds prioritized in silico will be tested in vitro (collaboration with PJ Corringer from Neuroscience Department Institut Pasteur).
In addition, the hypothesis that nAChRs are primary pharmacological targets against COVID-19 (Changeux et al 2020) is explored by in vivo studies about an eventual direct interaction with the virus with the nAChR protein (with PJ Corringer at Institut Pasteur) and by the in silico conception of new pharmacological agents against COVID-19 either by repurposing known allosteric modulators of nAChR such as ivermectin or by all-atom molecular dynamics to be tested in vivo in animal models against Covid 19 such as the Hamster model (with H Bourhy at Institut Pasteur).