一种由人丁酰胆碱酯酶改造而来的可卡因水解酶，作为涕灭威中毒的医学应对措施。
A cocaine hydrolase engineered from human butyrylcholinesterase as a medical countermeasure for aldicarb poisoning.
作者信息
LeSaint Johnathan E, Chandar Nellore Bhanu, Kyomuhangi Annet, Wei Huimei, Zheng Fang, Zhan Chang-Guo
机构信息
Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536, USA.
Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536, USA.
出版信息
Chem Biol Interact. 2025 Jul 31;420:111675. doi: 10.1016/j.cbi.2025.111675.
Aldicarb is known to be the most toxic carbamate pesticide and could be used easily by terrorists to cause a mass casualty incident. It is highly desired to discover a medical countermeasure for aldicarb poisoning. Based on structural insights from molecular modeling and in vitro experimental validation, CocH3-Fc(M3), a potent cocaine hydrolase engineered from human butyrylcholinesterase (BChE), has a ∼4-fold improved binding affinity with aldicarb compared to wild-type human acetylcholinesterase (AChE) and BChE and a 9-28-fold improved bimolecular rate constant for the carbamylation with aldicarb compared to AChE. CocH3-Fc(M3) also has significant catalytic activity for aldicarb hydrolysis and, hence, is identified as an aldicarb hydrolase. To the best of our knowledge, this is the first aldicarb hydrolase identified so far. Due to significant catalytic activity against aldicarb, CocH3-Fc(M3) effectively and dose-dependently rescued all mice that had been injected with a lethal dose of aldicarb, demonstrating the promise of CocH3-Fc(M3) as a potential medical countermeasure for aldicarb poisoning.
涕灭威是已知毒性最强的氨基甲酸酯类农药，很容易被恐怖分子利用来制造大规模伤亡事件。因此，迫切需要找到一种针对涕灭威中毒的医学应对措施。基于分子建模的结构见解和体外实验验证，从人丁酰胆碱酯酶（BChE）改造而来的强效可卡因水解酶CocH3-Fc(M3)，与野生型人乙酰胆碱酯酶（AChE）和BChE相比，对涕灭威的结合亲和力提高了约4倍，与AChE相比，涕灭威氨甲酰化的双分子速率常数提高了9至28倍。CocH3-Fc(M3)对涕灭威水解也具有显著的催化活性，因此被鉴定为一种涕灭威水解酶。据我们所知，这是迄今为止首次鉴定出的涕灭威水解酶。由于对涕灭威具有显著的催化活性，CocH3-Fc(M3)有效且剂量依赖性地挽救了所有注射致死剂量涕灭威的小鼠，证明了CocH3-Fc(M3)作为涕灭威中毒潜在医学应对措施的前景。
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