• 1 Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia 30602, United States
  • 2 United States Army Futures Command, Combat Capabilities Development Command, Chemical Biological Center, Chemcial Sciences Division, Agent Chemistry Branch, Aberdeen Proving Ground, Aberdeen, Maryland 21010-5424, United States
  • 3 New York Structural Biology Center, New York, New York 10027, United States
Chem Res Toxicol, 2021 03 15;34(3):804-816.
PMID: 33538594 DOI: 10.1021/acs.chemrestox.0c00406


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., 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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.