engleski

Detoxification of tabun-exposed mice by an acetylcholinesterase mutant assisted with a novel pyridinium aldoxime

Nerve agents, like tabun, are covalent inhibitors of acetylcholinesterase (AChE), an essential enzyme in neurotransmission whose inhibition may lead to death. The currently used therapy, consisting of an anticholinergic drug and an oxime as the reactivator of inhibited AChE is particularly ineffective in cases of tabun exposure, so finding an optimal reactivator is an ongoing effort. Click-chemistry, utilizing Cu (I)-catalyzed azide-alkyne cycloaddition of a library of small molecule building blocks, has made possible a rapid synthesis of a variety of new oximes. Among the new oximes tested in recent studies as reactivators of tabun-inhibited choline binding site AChE mutants, oxime 5B, a lengthened alkylchain congener of the standard oxime 2-PAM, stood out as a candidate for tabun ex vivo scavenging when paired with the Y337A mutant of AChE. Herein, we pursued the antidotal in vivo detoxification of tabun-exposed mice by assembling oxime-assisted catalytic scavenging using the mutant combined with oxime 5B. Although the antidotal treatment showed drawbacks, our findings offer a platform for further development of more potent means of counteracting tabun and related phosphoramidate exposure.

antidotes, bioscavengers, cholinesterase, nerve agents, organophosphorus compounds, 2PAM

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