Newly Designed Quinolinol Inhibitors Mitigate the Effects of Botulinum Neurotoxin A in Enzymatic, Cell-Based, and ex Vivo Assays

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• 作者：Paul T. BremerMichael Adler ; Cecilia H. Phung ; Ajay K. Singh ; Kim D. Janda
• 刊名：Journal of Medicinal Chemistry
• 出版年：2017
• 出版时间：January 12, 2017
• 年：2017
• 卷：60
• 期：1
• 页码：338-348
• 全文大小：576K
• ISSN：1520-4804

文摘

Botulinum neurotoxin A (BoNT/A) is one of the most deadly toxins and is the etiological agent of the potentially fatal condition, botulism. Herein, we investigated 8-hydroxyquinoline (quinolin-8-ol) as a potential inhibitor scaffold for preventing the deadly neurochemical effects of the toxin. Quinolinols are known chelators that can disrupt the BoNT/A metalloprotease zinc-containing active site, thus impeding its proteolysis of the endogenous protein substrate, synaptosomal-associated protein 25 (SNAP-25). By use of this information, the structure–activity relationship (SAR) of the quinolinol-5-sulfonamide scaffold was explored through preparation of a crude sulfonamide library and evaluation of the library in a BoNT/A LC enzymatic assay. Potency optimization of the sulfonamide hit compounds was undertaken as informed by docking studies, granting a lead compound with a submicromolar K_i. These quinolinol analogues demonstrated inhibitory activity in a cell-based model for SNAP-25 cleavage and an ex vivo assay for BoNT/A-mediated muscle paralysis.