Peptide Inhibitors of the α-Cobratoxin-Nicotinic Acetylcholine Receptor Interaction.

Journal of medicinal chemistry 2020 Nov 25

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Venomous snakebites cause >100 000 deaths every year, in many cases via potent depression of human neuromuscular signaling by snake α-neurotoxins. Emergency therapy still relies on antibody-based antivenom, hampered by poor access, frequent adverse reactions, and cumbersome production/purification. Combining high-throughput discovery and subsequent structure-function characterization, we present simple peptides that bind α-cobratoxin (α-Cbtx) and prevent its inhibition of nicotinic acetylcholine receptors (nAChRs) as a lead for the development of alternative antivenoms. Candidate peptides were identified by phage display and deep sequencing, and hits were characterized by electrophysiological recordings, leading to an 8-mer peptide that prevented α-Cbtx inhibition of nAChRs. We also solved the peptide:α-Cbtx cocrystal structure, revealing that the peptide, although of unique primary sequence, binds to α-Cbtx by mimicking structural features of the nAChR binding pocket. This demonstrates the potential of small peptides to neutralize lethal snake toxins in vitro, establishing a potential route to simple, synthetic, low-cost antivenoms.

Citation

Timothy Lynagh, Stephan Kiontke, Maria Meyhoff-Madsen, Bengt H Gless, Jónas Johannesen, Sabrina Kattelmann, Anders Christiansen, Martin Dufva, Andreas H Laustsen, Kanchan Devkota, Christian A Olsen, Daniel Kümmel, Stephan Alexander Pless, Brian Lohse. Peptide Inhibitors of the α-Cobratoxin-Nicotinic Acetylcholine Receptor Interaction. Journal of medicinal chemistry. 2020 Nov 25;63(22):13709-13718