engleski

Catalytic hydrolysis of tabun and soman utilizing cholinesterases and oximes

A high toxicity of nerve agents, tabun and soman, arises from the irreversible inhibition of acetylcholinesterase (AChE ; EC 3.1.1.7), important enzyme in cholinergic neurotransmission. The inhibition of AChE in central and peripheral tissue results in accumulation of neurotransmitter acetylcholine at vital cholinergic sites, which in turn leads to life-threatening toxic manifestations. Such poisonings call for immediate treatment, which usually consists of a combined administration of anticholinergic drugs and an oxime as the reactivator of AChE. However, this approach still has its limitations mostly due to the inability of currently applied reactivators to reactivate tissue AChE efficiently particularly when it is repeatedly phosphorylated by the excess of tabun or soman remaining in circulation upon exposure. Our recent studies have shown that AChE mutagenesis enables oximes to substantially accelerate the reactivation of the soman-enzyme conjugate that resists aging. We created human AChE mutant, Y337A/F338A, to combine the increased accessibility of conjugated phosphorus to oximes provided by the Y337A mutation with the aging resistance of the F338A mutation. On the other hand, we designed a library of new oximes where we identified efficient reactivators of the Y337A human AChE inhibited by tabun that accelerate reactivation rate for 10-times in comparison to the AChE w.t. Our overall findings indicate that distinct human AChE mutants have catalytic bioscavenging potential when combined with oximes, proven effective in soman or tabun in vitro exposure. (Supported by NIH UO1NS058046 and R21NS072086 and by IMROH 022-0222148-2889)

tabun; soman; acetylcholinestrase; human AChE mutant; bioscavening

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