engleski

Catalytic organophosphorus compounds scavenging by acetylcholinesterase assisted with aldoximes

The high toxicity of organophosphorus compounds (OP ; tabun, soman and VX) originates from the irreversible inhibition of acetylcholinesterase (AChE), an essential enzyme in cholinergic neurotransmission. Poisonings that lead to life‐threatening toxic manifestations call for immediate treatment, which usually consists of a combined administration of anticholinergic drugs and an aldoxime as the reactivator of AChE. A new approach to reduce the in vivo toxicity of OPs focuses on the use of bioscavengers – enzymes that could react with a nerve agent before it inhibits AChE. Butyrylcholinesterase (BChE), naturally present in plasma, the liver, the small intestine, smooth muscles, heart, adipose tissue, and the brain, is considered an endogenous stoichiometric bioscavenger of OP. Due to the limited concentration of BChE in the organism, a stoichiometric reduction of OP is not sufficient. Furthermore, the stoichiometric approach alone has limitations mostly due to the necessity to reactivate tissue AChE efficiently, particularly when it is repeatedly phosphorylated by an excess of OP that remain in circulation upon exposure. Our studies show that AChE mutagenesis enables aldoximes to substantially accelerate the reactivation of OP‐enzyme conjugates. We here demonstrate the oxime‐mutant hAChE assisted hydrolysis of OPs to be effective both ex vivo in human blood and in vivo in mice. The catalytic scavenging of OPs in mice improved the therapeutic outcome and resulted in a delayed onset of toxicity symptoms. Supported by the NIH (U01 NS058046 and R21NS072086) and CSF (4307)

tabun; soman; VX; reactivation

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