The recent use of organophosphate nerve agents in Syria, Malaysia, Russia, and the United Kingdom has reinforced the potential threat of their intentional release. These agents act through their ability to inhibit human acetylcholinesterase (hAChE; E.C. 3.1.1.7), an enzyme vital for survival. The toxicity of hAChE inhibition via G-series nerve agents has been demonstrated to vary widely depending on the G-agent used. To gain insight into this issue, the structures of hAChE inhibited by tabun, sarin, cyclosarin, soman, and GP were obtained along with the inhibition kinetics for these agents. Through this information, the role of hAChE active site plasticity in agent selectivity is revealed. With reports indicating that the efficacy of reactivators can vary based on the nerve agent inhibiting hAChE, human recombinatorially expressed hAChE was utilized to define these variations for HI-6 among various G-agents. 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 how the presence of G-agent adducts impacts reactivator access and placement within the active site. These insights will contribute toward a path of next-generation reactivators and an improved understanding of the innate issues with the current reactivators.
In recent assassinations reported in London and Malaysia, nerve agents were used to cause death, by skin poisoning. Skin decontamination is the ultimate and most important defense against nerve agent poisoning, because no effective antidote currently exists. However, almost no existing material can achieve effective and rapid decontamination without irritating the skin. This study links proteins that exhibit no decontamination ability with polymers to form a nanocomposite. This creates a nanospace on the surface of the protein that attracts and traps organic molecules, effectively adsorbing the nerve agent Soman within several seconds, without irritating the skin. Analysis of the different components of proteins and polymers reveals that the decontamination efficiency is considerably affected by the thickness of the coated polymer. Moreover, the thickness of the layer is predominantly determined by the size and species of the core and the crosslinking method. Further in vivo experiments on rats poisoned with Soman verify the efficiency and safety of the nanocomposite. These results could be used to design and synthesize more multi-functional and effective decontamination materials.