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

ABSTRACT: Venomous snakebites cause >100 000 deaths every year, in many cases via potent depression of human neuromuscular signaling by snake ?-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 ?-cobratoxin (?-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 ?-Cbtx inhibition of nAChRs. We also solved the peptide:?-Cbtx cocrystal structure, revealing that the peptide, although of unique primary sequence, binds to ?-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.

SUBMITTER: Lynagh T 

PROVIDER: S-EPMC7705965 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature