Novel Treatments for Botulism: Development of Antagonists for Identified Steps inthe Action of Botulinum Neurotoxins

摘要

Using a combination of electrophysiological and biochemical techniques, theaction of botulinum neurotoxin (BoNT) was shown conclusively to involve (1) binding/ targetting to ecto-acceptors on cholinergic neurons, (2) acceptor-mediated uptake and, (3) block of Ca24-dependent release of transmitters. Domains/chains in BoNT responsible for each step were identified. One useful antagonist of the toxin's binding was developed, in addition to a monoclonal antibody capable of neutralizing the intracellular poisoning. Insights into the molecular action of BoNT were gained, particularly involvement of microtubules in the base of B and, possible, a large phosphorylated protein concerned with exocytosis. Equivalent experiments on tetanus toxin, and chimeric mixtures of both toxins, yielded valuable information for possible future targetting of agents to cholinergic and non-cholinergic neurons. A more detailed summary is included in the report.