The project aims at taking advantage of the potential of underexploited venoms to discover and characterize valuable modulators of SK and HCN 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 seek for 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 co-PIs of this study are the Dr Alain Brans (Protein synthesis, InBios, Sciences Faculty), le Dr Frédéric Kerff (Cristallography, InBios, Sciences Faculty), le Prof. Vincent Seutin (Pharmacology, Medecine Faculty) et le Prof. Jean-François Liégeois (Drug Design,CIRM, Medecine Faculty).