engleski

Assessment of pralidoxime analogues as efficient reactivators of butyrylcholinesterase inhibited by organophosphates

The toxicity of organophosphorus compounds (OPs) remains a major public health concern due to their widespread use as pesticides and the existence of nerve agents. Their common mechanism of action involves the inhibition of enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) which are crucial for neurotransmission. Both chronic and acute poisoning by OPs can leave long-lasting health effects even when patients are treated with standard medical therapy. No oxime used for medicinal and military purposes, such as pralidoxime (2-PAM), obidoxime and asoxime, is a universal AChE reactivator. General reason for it is the structural variability of OPs and the fact that reactivation depends on a nucleophilic displacement of the OP moiety bound to the catalytic serine of cholinesterase enzymes. Moreover, standard oximes are less efficient reactivators of OP-inhibited BChE than they are for OP-inhibited AChE ; and still no oxime has shown exceptional improvement in BChE reactivation. Therefore, an increasing urgency exists to find more effective oxime reactivators for compounds resistant to reactivation, especially phosphoramidates (tabun, Novichoks, etc). Our recent results on 2-PAM analogs have shown remarkable improvement in reactivation of AChE inhibited by tabun and tabun analogues (mathamidophos and fenamiphos). Moreover, the oximes introduced an even greater improvement in BChE reactivation, which was shown to be a 300 times more efficient reactivation than that obtained with 2PAM in the case of cyclosarin inhibition. Further ex vivo testing of selected oximes and BChE confirmed efficient oxime-assisted catalytic bioscavenging and neutralizing of OP exposure in whole blood. Our findings offer a platform for further antidote and scavenger development for exposure to organophosphates. Acknowledgments: This work was supported by the Croatian Science Foundation (IP-2018-01-7683).

PAM, butyrylcholinesterase, nerve agents, oximes

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