A Novel, Modified Human Butyrylcholinesterase Catalytically Degrades the Chemical Warfare Nerve Agent, Sarin

丁酰胆碱酯酶 神经毒剂 乙酰胆碱酯酶 沙林 索曼 胆碱能的 化学战剂 化学 胆碱酯酶 药理学 毒性 阿切 生物化学 生物 神经科学 有机化学 生化工程 工程类
作者
Kevin G. McGarry,Rémy F. Lalisse,Robert A. Moyer,Kristyn M Johnson,Alexi Tallan,Tyson P Winters,Joseph E. Taris,Craig A. McElroy,Erin E Lemmon,Hannah S. Shafaat,Yamin Fan,Aniliese Deal,Sean C. Marguet,Jill A. Harvilchuck,Christopher M. Hadad,David W. Wood
出处
期刊:Toxicological Sciences [Oxford University Press]
卷期号:174 (1): 133-146 被引量:5
标识
DOI:10.1093/toxsci/kfz251
摘要

Abstract Chemical warfare nerve agents (CWNAs) present a global threat to both military and civilian populations. The acute toxicity of CWNAs stems from their ability to effectively inhibit acetylcholinesterase (AChE). This inhibition can lead to uncontrolled cholinergic cellular signaling, resulting in cholinergic crisis and, ultimately, death. Although the current FDA-approved standard of care is moderately effective when administered early, development of novel treatment strategies is necessary. Butyrylcholinesterase (BChE) is an enzyme which displays a high degree of structural homology to AChE. Unlike AChE, the roles of BChE are uncertain and possibilities are still being explored. However, BChE appears to primarily serve as a bioscavenger of toxic esters due to its ability to accommodate a wide variety of substrates within its active site. Like AChE, BChE is also readily inhibited by CWNAs. Due to its high affinity for binding CWNAs, and that null-BChE yields no apparent health effects, exogenous BChE has been explored as a candidate therapeutic for CWNA intoxication. Despite years of research, minimal strides have been made to develop a catalytic bioscavenger. Furthermore, BChE is only in early clinical trials as a stoichiometric bioscavenger of CWNAs, and large quantities must be administered to treat CWNA toxicity. Here, we describe previously unidentified mutations to residues within and adjacent to the acyl binding pocket (positions 282–285 were mutagenized from YGTP to NHML) of BChE that confer catalytic degradation of the CWNA, sarin. These mutations, along with corresponding future efforts, may finally lead to a novel therapeutic to combat CWNA intoxication.
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