Institute for Medical Research and Occupational Health, Ksaverska cesta 2, HR-10001, Zagreb, Croatia.
Institute for Medical Research and Occupational Health, Ksaverska cesta 2, HR-10001, Zagreb, Croatia.
Neuropharmacology. 2020 Jul;171:108111. doi: 10.1016/j.neuropharm.2020.108111. Epub 2020 Apr 22.
The recent advancements in crystallography and kinetics studies involving reactivation mechanism of acetylcholinesterase (AChE) inhibited by nerve agents have enabled a new paradigm in the search for potent medical countermeasures in case of nerve agents exposure. Poisonings by organophosphorus compounds (OP) that lead to life-threatening toxic manifestations require immediate treatment that combines administration of anticholinergic drugs and an aldoxime as a reactivator of AChE. An alternative approach to reduce the in vivo toxicity of OP centers on the use of bioscavengers against the parent organophosphate. Our recent research showed that site-directed mutagenesis of AChE can enable aldoximes to substantially accelerate the reactivation of OP-enzyme conjugates while dramatically slowing down rates of OP-conjugate dealkylation (aging). Therefore, this review focuses on oxime-assisted catalysis by AChE mutants that provides a potential means for degradation of organophosphates in the plasma before reaching the cellular target site. This article is part of the special issue entitled 'Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield'.
近年来，晶体学和动力学研究的进展涉及到神经毒剂抑制的乙酰胆碱酯酶（AChE）的重激活机制，为寻找针对神经毒剂暴露的有效医疗对策提供了新的范例。有机磷化合物（OP）中毒会导致危及生命的毒性表现，需要立即进行治疗，包括使用抗胆碱能药物和肟类化合物作为 AChE 的重激活剂。减少 OP 体内毒性的另一种方法是使用生物清除剂对抗母体有机磷酸酯。我们最近的研究表明，AChE 的定点突变可以使肟类化合物大大加速 OP-酶结合物的重激活，同时显著降低 OP-结合物的脱烷基化（老化）速率。因此，本文重点介绍了 AChE 突变体的肟辅助催化作用，为在到达细胞靶位之前在血浆中降解有机磷酸酯提供了一种潜在的方法。本文是题为“乙酰胆碱酯酶抑制剂：从实验室到临床再到战场”的特刊的一部分。
