Investigating novel therapeutic targets and molecular mechanisms to treat botulinum neurotoxin A intoxication.

Botulinum neurotoxin (BoNT) has recently catapulted into the public consciousness in two seemingly disparate roles: potential use as a biological weapon and treatment of neuromuscular disorders. This bacterially produced protein is the most potent toxin known to humans, with a lethal dose estimated at approximately 1 ng/kg of body weight. BoNT intoxication occurs via a multistep process that includes recognition of peripheral neuronal cell membrane receptors, endocytosis and translocation of the light chain metalloprotease into the cytosol, and catalytic cleavage of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins critical for vesicle fusion and neurotransmitter release. Each of these distinct steps has been studied at the molecular level and is a valid target for the development of pharmacological interventions to prevent the considerable mortality associated with botulism. Alternatively, clinical uses of BoNT continue to expand at an ever-increasing rate; however, further optimization of BoNT therapy is critical to maximize efficacy.