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.
The Scripps Research Institute, Department of Chemistry, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. eubanks@scripps.edu
Lisa M
LM
Eubanks
Tobin J
TJ
Dickerson
D019274:Botulinum Toxins, Type A / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D008565:Membrane Proteins / Q000032:analysis; D009419:Nerve Tissue Proteins / Q000032:analysis; D009474:Neurons / Q000187:drug effects*; D018377:Neurotransmitter Agents / Q000378:metabolism; D050600:SNARE Proteins / Q000378:metabolism*
D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D050600:SNARE Proteins; D019274:Botulinum Toxins, Type A