engleski

Pseudo-catalytic nerve agents scavenging by acetylcholinesterase assisted with aldoximes

Poisoning caused by the nerve agents calls for immediate treatment, which usually consists of a combined administration of an anticholinergic drug and an oxime as the reactivator of the enzyme acetylcholinesterase (AChE). Newly considered strategies in medical protection against nerve agents focus on the use of exogenously administered butyrylcholinesterase (BChE). The overall idea is to administer such an enzyme in combination with a specific oxime, to scavenge an organophosphate (OP) before it can reach and inhibit native acetylcholinesterase (AChE), thus helping organism detoxification from the excess OP. However, oxime antidotes commonly used to reactivate OP inhibited AChE are ineffective against soman and tabun, while the efficacy of the recommended nerve agent bioscavenger BChE is limited by strictly stoichiometric scavenging. 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 its 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 (4307).

acetylcholinesterase, scavengers, antidote, oxime, nerve agents

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