Loïc Quinton (University of Liège) has obtained a new project, funded by the F.R.S – FNRS funding body. The 4-year funded project, which started on 1st January 2021, is called: “Venoms4Liège: From mortal mixtures to innovative pharmacological tools: venoms as ligand providers for the promising molecular ion channels SK and HCN.”
The project aims at taking advantage of the potential of underexploited venoms to discover and characterize valuable modulators of SK (small conductance calcium-activated potassium channels) and HCN (Hyperpolarisation-activated Cyclic Nucleotide-gated channels) ion channels. These receptors are targets of high interest for the understanding of the central nervous system functions. Indeed, the huge potential of animal venoms to provide highly selective ligands of cell receptors is not questionable, scorpions are, for example, among the most remarkable producers of toxins affecting ion channels. In this context, our project, VenomsForLiège proposes to deeply investigate 40 crude venoms to discover atypical and innovative ligands for SK and HCN ion channels. The workflow will start with a MS-based fast affinity screening to allow a rational selection of the most promising venomous species for our study. The latter will be analyzed through an integrated methodology combining sourcing of the species, transcriptomics (venom glands), proteomics (crude venoms), peptide production (recombinant synthesis, purification and folding) and electrophysiological characterization to look for highly selective ligands for SK and HCN channels. The toxin-receptor complexes will finally be modeled by the help of cryo electron microscopy to understand the mechanism of action of such toxins. The tools and methods developed for this project will be applied similarly to support the development of new peptidic compounds, but also non-peptidic ones, with potential therapeutic applications (drug design). The proposed approach combines a low risk study, as SK modulators have already been described in bee and scorpion venoms giving us a chance of rather high success, and a more exploratory one as HCN–selective toxins, to our knowledge, have not yet been discovered.