Discovery of Dipeptides as Potent Botulinum Neurotoxin A Light-Chain Inhibitors
Discovery of Dipeptides as Potent Botulinum Neurotoxin A Light-Chain Inhibitors
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DOI：
10.1021/acsmedchemlett.0c00674
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发表时间：
2021-01-27
影响因子：
4.2
通讯作者：
Salzameda, Nicholas T.
中科院分区：
文献类型：
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作者：
Amezcua, Martin;Cruz, Ricardo S.;Salzameda, Nicholas T.
肉毒杆菌神经毒素是引起肉毒杆菌中毒的腐蚀剂，是人类已知的最致命的毒素。由重链（HC）和轻链（LC）组成的神经毒素进入神经元并切割SNARE蛋白，导致弛缓性麻痹，严重时可导致死亡。肉毒杆菌神经毒素（BoNT）中毒的治疗靶标是LC，其是直接切割SNARE蛋白的锌金属蛋白酶。在本文中，我们报告含有通过磺酰胺和异羟肟酸在C-末端作为BoNT/A LC抑制剂连接到N-末端的芳香族的二肽。基于结构-活性关系研究，发现33以21 nM的IC 50抑制BoNT/A LC。30和33的X-射线晶体学分析显示，二肽通过竞争机制抑制，并确定了几个关键的分子间相互作用。
The botulinum neurotoxin, the caustic agent that causes botulism, is the most lethal toxin known to man. The neurotoxin composed of a heavy chain (HC) and a light chain (LC) enters neurons and cleaves SNARE proteins, leading to flaccid paralysis, which, in severe occurrences, can result in death. A therapeutic target for botulinum neurotoxin (BoNT) intoxication is the LC, a zinc metalloprotease that directly cleaves SNARE proteins. Herein we report dipeptides containing an aromatic connected to the N-terminus via a sulfonamide and a hydroxamic acid at the C-terminus as BoNT/A LC inhibitors. On the basis of a structure- activity relationship study, 33 was discovered to inhibit the BoNT/A LC with an IC50 of 21 nM. X-ray crystallography analysis of 30 and 33 revealed that the dipeptides inhibit through a competitive mechanism and identified several key intermolecular interactions.