Development of a Broad-Spectrum Oxime for the Treatment of Nerve Agent Toxicity

Abstract : 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 HI-6 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.