Design, selection and validation of nicotinic acetylcholine receptor mimicking molecules as novel ‘decoy receptor’ therapies for treating snakebite
Prof Chris Ulens
Katholieke Universiteit Leuven, Belgium
One of the most common lethal snakebite pathologies is neurotoxicity. This is the result of neurotoxins blocking nerve transmission, commonly via interaction with nicotinic acetylcholine receptors (nAChRs).
We will use molecules that mimic the structural components of nAChRs, that are important for toxin binding, to generically inhibit the functional activity of venom neurotoxins. Our pilot data demonstrates that such ‘decoy receptors’ offer great potential to generically neutralise venom neurotoxins irrespective of snake species (unlike antivenom).
We will use structural and informatic guided approaches to rationally design a panel of acetylcholine receptor binding proteins, nAChR ligand binding domains, and peptide mimotopes, before measuring their binding affinity to venom neurotoxins. We will then identify the toxins they capture using analytical approaches, before demonstrating that they effectively prevent binding to nAChRs.
We will then use in vivo efficacy studies to robustly assess whether mixtures of lead decoy receptors protect mice from venom lethality, as either solo or adjunct therapies. We anticipate that our inhibitory mixtures will exhibit superiority over antivenom, by neutralising neurotoxins irrespective of the snake species and at lower therapeutic doses. This project therefore has the potential to generate a single, generic, eminently translatable therapy for treating neurotoxic snakebites worldwide.