We describe here the state of the art of certain aspects concerning potential small molecule therapy directed toward
botulism, by inhibition of the zinc-protease containing light chain (LC) of botulinum neurotoxin BoNT/A from the
anaerobic bacillus Clostridium botulinum. Botulinum neurotoxins (BoNTs) are comprised of eight serologically-distinct
proteins (A – H), several of which are further divided, such as BoNT/A which has five subtypes. The BoNTs are the most
toxic substances known to mankind, causing a form of flaccid paralysis that can be rapid and is often lethal. BoNT/A is
comprised of a ~100 kDa heavy chain (HC) attached via a single disulfide Cys-Cys bond to a ~50 kDa LC. The HC mediates
transport to and uptake by presynaptic glutamatergic neurons, where the LC cleaves the protein SNAP-25 and thus
prevents vesicular trafficking and release of acetylcholine. The Zn-endoprotease activity of the LC of BoNT/A is a target
for the development of small molecule inhibitors of BoNT/A-mediated toxicity. A variety of BoNT/A LC inhibitors have
been described to date and we focus here primarily on the Zn-binding 8-hydroxyquinoline structural type as well as some
of the previously-described hydroxamic acids.
Keywords: 8-hydroxyquinolines, bioterrorism, BoNT/A, botulinum neurotoxin, botulism, hydroxamic acids, small-molecule
protease inhibitors, structural biology, Zinc protease.
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