engleski

Acetylcholinesterase and novel oxime reactivators in counteracting organophosphate exposure

The high toxicity of organophosphorus compounds (OPs ; tabun, sarin, cyclosarin VX and soman) originates from the irreversible inhibition of acetylcholinesterase (AChE), an essential enzyme in cholinergic neurotransmission. Poisonings lead to life-threatening toxic manifestations and call for immediate treatment, which usually consists of combined administration of a muscarinic antagonist and an aldoxime as the reactivator of AChE. Our previous research showed that AChE mutagenesis can enable oximes to substantially accelerate the reactivation of OP-enzyme conjugates, while dramatically slowing down rates of OP-conjugate dealkylation (aging). Here we analyzed the reactivation of phosphoramidate conjugates of AChE by nearly 130 novel oximes synthesized using largely a [3+2] cycloaddition between alkyne and azide building blocks. We identified several oximes with significantly improved human AChE-reactivating efficacy against the phosphoramidate OP conjugates and antidotal efficacy of tabun exposure in mice. We furthermore screened the same library for the reactivation activity of two AChE mutants inhibited by tabun, and identified a distinctive rank order of potency and more effective reactivators of the phosphoramidated mutant AChE when compared with the wild type AChE. Further ex vivo testing of selected oximes and AChE mutants confirmed efficient oxime-assisted catalytic bioscavenging and neutralizing of OP exposure in whole blood. Our findings offer an expanded platform for further antidote and scavenger development for exposure to organophosphates. (Supported by the Croatian Science Foundation (4307)

nerve agents, bioscavengers, antidotes, cholinesterases

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