期刊
CURRENT TOPICS IN MEDICINAL CHEMISTRY
卷 14, 期 18, 页码 2094-2102出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1568026614666141022095114
关键词
8-hydroxyquinolines; bioterrorism; BoNT/A; botulinum neurotoxin; botulism; hydroxamic acids; small-molecule protease inhibitors; structural biology; Zinc protease
资金
- National Institutes of Health [AI082190]
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 similar to 100 kDa heavy chain (HC) attached via a single disulfide Cys-Cys bond to a similar to 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.
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