Development of a Broad-spectrum Oxime for the Treatment of Nerve Agent Toxicity
نویسنده
چکیده
Inhibition of synaptic acetylcholinesterase (AChE) by organophosphate (OP) nerve agents is the main reason for their toxicity. Oximes are used as antidotes to reactivate nerve agent-inhibited AChE. To understand the mechanism of oxime-induced reactivation, we generated several mutant AChEs. Reactivation studies conducted with wild-type and mutant AChEs revealed that the peripheral anionic site of AChE plays a critical role in the reactivation of nerve agent-inhibited AChE by bis-pyridinium oximes, and not by mono-pyridinium oximes. Results showed that Y124 is an important determinant for the enhanced reactivation potency of HI6 and HLo-7. Results also suggest that both the second pyridinium structure and the ether oxygen of HI-6 and HLo-7 are involved in interactions with the peripheral anionic site of AChE. These interactions are important considerations for the development of a next generation broad-spectrum oxime.
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