8-Hydroxyquinoline and Hydroxamic Acid Inhibitors of Botulinum Neurotoxin BoNT/A

Author(s): Tobin J. Dickerson, Garry R. Smith, Jeffrey C. Pelletier, Allen B. Reitz.

Journal Name: Current Topics in Medicinal Chemistry

Volume 14 , Issue 18 , 2014

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Abstract:

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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Article Details

VOLUME: 14
ISSUE: 18
Year: 2014
Page: [2094 - 2102]
Pages: 9
DOI: 10.2174/1568026614666141022095114
Price: $58

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