engleski

Pralidoxime analogues and acetylcholinesterase mutants in counteracting tabun poisoning

Acetylcholinesterase (AChE) is a pivotal enzyme with a role in the degradation of nerve impulses. Its activity can be irreversibly inhibited by organophosphates (OPs) acting as nerve agents and pesticides. Compounds with an oxime group (2-PAM, HI-6, obidoxime) can restore phosphylated AChE activity and the success of reactivation depends on the OP conjugated to AChE. Tabun is one of the most dangerous nerve agents and is known to cause severe symptoms of poisoning often with deadly outcomes. The electron pair located on the tabun´s phosphoramide group and the formation of the steric hindrance within the AChE active centre gorge upon formation of AChE-tabun conjugate unfavourably affect the oxime orientation and its embedding in the vicinity of the phosphorylated catalytic serin disenabling AChE reactivation. Pralidoxime (2-PAM) is the oxime of choice of many worldwide armies, but with limited potency. The efficacy of nerve agent exposure therapy is supplemented by AChE mutants which could in combination with the oxime degrade the OP in cycles before it inhibits the native AChE. In this study, a series of 2-PAM analogues were tested as a reactivator of tabun-inhibited AChE and its mutants. The most promising was the analogue with a hexyl chain which in vitro and ex vivo restored a high percent of phosphorylated AChE activity in a short time. Nevertheless, experiments on mice failed to prove the efficacy of this treatment in vivo and further adjustment of the dose or route of administration could possibly enhance it. Acknowledgement: The authors thank Professors P. Taylor and K. B. Sharpless for the generous gift of cholinesterases and oximes.

cholinesterases ; detoxification ; nerve agent ; oxime ; reactivator

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