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Abstract
The toxicity of irreversible human acetylcholinesterase inhibition, via G-series nerve agents, potentially relies on the unique accommodation of the inhibitor. Therapeutic compounds that reverse human acetylcholinesterase (hAChE) inhibition, known as reactivators, vary in efficacy depending on multiple factors including the particular nerve agent present. The oxime reactivator, HI-6, shows particularly low activity on tabun (GA)-inhibited hAChE, but can reactivate hAChE inhibited by other G-series agents to varying degrees, including sarin (GB) and soman (GD). To gain insight into this issue, the structures of hAChE inhibited by tabun, sarin, cyclosarin, soman, and GP were obtained though X-ray crystal diffraction. In addition, the inhibition and reactivation kinetics for these agents were obtained through the use of a modified Ellman’s assay. To identify the structural underpinnings of this phenomenon, the structures of tabun, sarin, and soman-inhibited hAChE in complex with HI-6 were determined. This revealed the impact of the nerve agent adduct on reactivator access and placement within the active site. These insights will contribute towards a path of next generation reactivators and an improved understanding of the innate issues with the current reactivators.