engleski

Detoxification of Nerve Agents by Oxime-Assisted Reactivation of Cholinesterases

The high toxicity of organophosphorus compounds originates from covalent inhibition of acetylcholinesterase (AChE), an essential enzyme in cholinergic neurotransmission. Poisonings 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 OPs focuses on the use of bioscavengers, such as related enzyme butyrylcholinesterase (BChE), against the parent organophosphate. Our previous research showed that AChE mutagenesis can enable aldoximes to substantially accelerate the reactivation of OP-enzyme conjugates, while dramatically slowing down rates of OP-conjugate dealkylation (aging). Herein we demonstrated through a combination of in silico, in vitro, ex vivo, and in vivo results, a feasible approach to the development of an oxime assisted catalytic bioscavenger of soman, tabun and VX based on human AChE mutants modified at the choline binding site (Y337A and an aging resistant Y337A/F338A) in combination with their efficient reactivator. Ultimately, the oxime assisted catalytic scavenging of the nerve agents in mice improved therapeutic outcomes preventing lethality and resulted in a delayed onset of toxicity symptoms. Acknowledgments This work was supported by the Croatian Science Foundation (IP-2018-01-7683).

detoxification, nerve agents, cholinesterase

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