8-Hydroxyquinoline and hydroxamic acid inhibitors of botulinum neurotoxin BoNT/A.
8-Hydroxyquinoline and hydroxamic acid inhibitors of botulinum neurotoxin BoNT/A.
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DOI：
10.2174/1568026614666141022095114
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发表时间：
2014-08
影响因子：
3.4
通讯作者：
T. Dickerson;Garry R. Smith;J. Pelletier;A. Reitz
中科院分区：
文献类型：
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作者：
T. Dickerson;Garry R. Smith;J. Pelletier;A. Reitz
在此，我们描述了针对肉毒中毒的潜在小分子疗法某些方面的最新进展，即通过抑制来自厌氧芽孢杆菌肉毒梭菌的含锌蛋白酶的肉毒神经毒素BoNT/A轻链（LC）。肉毒神经毒素（BoNTs）由八种血清学上不同的蛋白质（A - H）组成，其中一些还进一步细分，例如BoNT/A有五种亚型。肉毒神经毒素是人类已知的毒性最强的物质，会导致一种弛缓性麻痹，发病迅速且往往致命。BoNT/A由一条约100 kDa的重链（HC）通过一个二硫键（Cys - Cys）与一条约50 kDa的轻链相连。重链介导向突触前谷氨酸能神经元的运输和摄取，在那里轻链切割蛋白质SNAP - 25，从而阻止囊泡运输和乙酰胆碱的释放。BoNT/A轻链的锌内肽酶活性是开发BoNT/A介导的毒性的小分子抑制剂的一个靶点。到目前为止，已经描述了多种BoNT/A轻链抑制剂，在此我们主要关注结合锌的8 - 羟基喹啉结构类型以及一些先前描述的异羟肟酸。
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.