title: A platform stratifying a sequestering agent and a pharmacological antagonist as a means to negate botulinum neurotoxicity.
abstract: Botulinum neurotoxicity is characterized by peripheral neuromuscular blockade/flaccid paralysis that can lead to respiratory failure and ultimately death. Current therapeutic options provide relief in a pre-exposure scenario, but there are no clinically approved postexposure medical countermeasures. Here, we introduce a platform that utilizes a combination of a toxin sequestering agent and a pharmacological antagonist to ablate botulinum neurotoxicity in a well-defined mouse lethality assay. The platform was constructed to allow for ready exchange of sequestering agent and/or pharmacological antagonist for therapeutic optimization. As such, we attempted to improve upon the pharmacological antagonist, a potassium channel blocker, 3,4-diaminopyridine, through a prodrug approach; thus, a complete kinetic decomposition pathway is described. These experiments provide the first proof-of-principle that a synergistic combination strategy can be used to reduce toxin burden in the peripheral using a sequestering antibody, while restoring muscle action via a pharmacological small molecule antagonist.
authors.affiliation: Departments of Chemistry, Immunology and Microbial Sciences, and The Skaggs Institute for Chemical Biology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Tyler L
authors.initials: TL
authors.lastname: Harris
authors.forename: Colin A
authors.initials: CA
authors.lastname: Lowery
authors.forename: Mark S
authors.initials: MS
authors.lastname: Hixon
authors.forename: Kim D
authors.initials: KD
authors.lastname: Janda
mesh_terms: D015761:4-Aminopyridine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000077770:Amifampridine; D000818:Animals; D001904:Botulinum Antitoxin / Q000494:pharmacology; D001905:Botulinum Toxins / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D004359:Drug Therapy, Combination; D005260:Female; D007700:Kinetics; D051379:Mice; D020258:Neurotoxicity Syndromes / Q000097:blood / Q000188:drug therapy*; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D064449:Sequestering Agents / Q000494:pharmacology*; D016019:Survival Analysis
chemical_list: D001904:Botulinum Antitoxin; D026902:Potassium Channel Blockers; D064449:Sequestering Agents; D015761:4-Aminopyridine; D001905:Botulinum Toxins; D000077770:Amifampridine