发现二肽作为有效的肉毒杆菌神经毒素A轻链抑制剂。
Discovery of Dipeptides as Potent Botulinum Neurotoxin A Light-Chain Inhibitors.
作者信息
Amezcua Martin, Cruz Ricardo S, Ku Alex, Moran Wilfred, Ortega Marcos E, Salzameda Nicholas T
机构信息
Department of Chemistry & Biochemistry, California State University, Fullerton, California 92831, United States.
出版信息
ACS Med Chem Lett. 2021 Jan 27;12(2):295-301. doi: 10.1021/acsmedchemlett.0c00674. eCollection 2021 Feb 11.
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, was discovered to inhibit the BoNT/A LC with an IC of 21 nM. X-ray crystallography analysis of and revealed that the dipeptides inhibit through a competitive mechanism and identified several key intermolecular interactions.
肉毒杆菌神经毒素是导致肉毒中毒的腐蚀性物质，是人类已知的最致命毒素。这种由重链（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）中毒的一个治疗靶点是轻链，它是一种直接切割SNARE蛋白的锌金属蛋白酶。在此，我们报告了一类二肽，其N端通过磺酰胺连接一个芳香基团，C端为异羟肟酸，作为BoNT/A轻链抑制剂。基于构效关系研究，发现该二肽以21 nM的IC抑制BoNT/A轻链。对该二肽的X射线晶体学分析表明，这些二肽通过竞争机制发挥抑制作用，并确定了几个关键的分子间相互作用。
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