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

Timothy Lynagh*, Stephan Kiontke, Maria Meyhoff-Madsen, Bengt H Gless, Jónas Johannesen, Sabrina Kattelmann, Anders Christiansen, Martin Dufva, Andreas H. Laustsen, Kanchan Devkota, Christian Adam Olsen, Daniel Kümmel, Stephan Alexander Pless, Brian Lohse

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

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.
Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume63
Pages (from-to)13709−13718
ISSN0022-2623
DOIs
Publication statusPublished - 2020

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