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.

A Platform Stratifying a Sequestering Agent and a Pharmacological Antagonist as a Means to Negate Botulinum Neurotoxicity

“…Furthermore, providing more than transient efficacy requires the use of an osmotic minipump. , As such, any potential clinical treatment utilizing an aminopyridine would require continuous intravenous infusion or a repeated dose regimen. Notwithstanding the negative side effects associated with aminopyridines, our data indicates its potential as an effective treatment of BoNT/A in mouse models, especially over other K + channel blockers such as scorpion venom derived peptides . Thus, we invoked the development of a prodrug in an effort to improve the pharmacokinetic properties of 3,4-DAP.…”

“…Notwithstanding the negative side effects associated with aminopyridines, our data indicates its potential as an effective treatment of BoNT/A in mouse models, especially over other K + channel blockers such as scorpion venom derived peptides. 12 Thus, we invoked the development of a prodrug in an effort to improve the pharmacokinetic properties of 3,4-DAP. Recently, our laboratory applied a prodrug approach to create carbamate/amide-ester conjugates of 3,4-DAP with the dual intent of inhibiting acetylcholinesterease and releasing localized 3,4-DAP at the synaptic cleft.…”

“…Conversely, a pharmacological antagonist can enter the nerve cell and in theory should temporarily reduce the paralytic effects of BoNT. Unfortunately, no small molecule has been approved for the treatment of botulism, although K + channel blockers and protease inhibitors have been touted as potential leads. − A major impediment in the advancement of these compounds is their inherently short half-life relative to that of BoNT, which depending on the serotype can exist for months in humans . Thus, small molecules may provide temporary relief but sustained administration would be required over the duration of BoNT intoxication, as the compounds are unable to eliminate toxin circulation in the periphery.…”