title: Scorpion toxins for the reversal of BoNT-induced paralysis.
abstract: The botulinum neurotoxins, characterized by their neuromuscular paralytic effects, are the most toxic proteins known to man. Due to their extreme potency, ease of production, and duration of activity, the BoNT proteins have been classified by the Centers for Disease Control as high threat agents for bioterrorism. In an attempt to discover effective BoNT therapeutics, we have pursued a strategy in which we leverage the blockade of K(+) channels that ultimately results in the reversal of neuromuscular paralysis. Towards this end, we utilized peptides derived from scorpion venom that are highly potent K(+) channel blockers. Herein, we report the synthesis of charybdotoxin, a 37 amino acid peptide, and detail its activity, along with iberiotoxin and margatoxin, in a mouse phrenic nerve hemidiaphragm assay in the absence and the presence of BoNT/A.
authors.affiliation: Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA; Department of Immunology and Microbial Sciences, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Lowery
authors.forename: Michael
authors.initials: M
authors.lastname: Adler
authors.forename: Andrew
authors.initials: A
authors.lastname: Borrell
authors.forename: Kim D
authors.initials: KD
authors.lastname: Janda
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001905:Botulinum Toxins; D018999:Charybdotoxin / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D010243:Paralysis / Q000139:chemically induced* / Q000188:drug therapy*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D010791:Phrenic Nerve / Q000187:drug effects*; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D012117:Resins, Synthetic / Q000737:chemistry; D012604:Scorpion Venoms / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D010455:Peptides; D026902:Potassium Channel Blockers; D012117:Resins, Synthetic; D012604:Scorpion Venoms; D018999:Charybdotoxin; C077910:margatoxin; C064719:iberiotoxin; D001905:Botulinum Toxins
keywords: Aminopyridine; Bioterrorism; Botulinum neurotoxin; Phrenic nerve hemidiaphragm; Scorpion toxin