N-terminal PEGylation enhances organophosphorus hydrolase catalysis for a promising fast and long-acting prophylactic candidate
文献类型： 外文期刊
作者： Ma, Ming 1 ; Zhai, Yanan 1 ; Jin, Qiantong 2 ; Wang, Dan 1 ; Wang, Shunye 1 ; Liu, Zhuang 1 ; Wang, Ziyang 1 ; Wang, Chengcai 1 ; Xie, Yanwei 1 ; Ren, Zilin 2 ; Gao, Xiang 1 ; Gao, Jing 1 ;
作者机构： 1.Beijing Inst Pharmacol & Toxicol, State Key Lab Natl Secur Specially Needed Med, Beijing 100850, Peoples R China
2.Changchun Vet Res Inst, Chinese Acad Agr Sci, State Key Lab Pathogen & Biosecur, Key Lab Jilin Prov Zoonosis Prevent & Control, Changchun 130012, Peoples R China
关键词： Organophosphorus compounds (OPs); Bioscavenger; Organophosphorus hydrolase; Polyethylene glycol (PEG); MD simulation
期刊名称：JOURNAL OF HAZARDOUS MATERIALS （ 影响因子：11.3； 五年影响因子：12.4 ）
ISSN： 0304-3894
年卷期： 2025 年 488 卷
页码：
收录情况： SCI
摘要： Organophosphorus compounds (OPs) poisoning poses a significant health risk as an insecticide, and its potent toxicity is characterized by rapid onset and a very narrow window for intervention. Prophylactic medication is crucial for managing OPs poisoning, yet effective and safe drugs are still lacking. The enzyme Organophosphorus hydrolase (OPH) shows promise as a bioscavenger but faces challenges due to its short half-life and strong immunogenicity. Our research reveals that N-terminal PEGylation of OPH significantly extends its pharmacokinetic half-life, reduces immunogenicity, and, surprisingly, enhances its catalytic activity for ethyl paraoxon. Intravenous administration of PEGY40kDa-OPH at a dose of 1 mg/kg effectively protected the rats against 4 doses of 2 xLD50 ethyl paraoxon challenge with neither death nor toxic symptoms observed. Molecular dynamics simulations suggest that this enhancement is due to increased flexibility and stronger hydrogen bonding between the active site of PEGylated OPH and the substrate. This leads to more stable binding and higher catalytic rate. The study offers a strategy for a rapid and enduring prophylactic against organophosphorus poisoning and introduces a new analytical approach to understand the impact of PEGylation on enzymatic function.
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