2025-07-14 ローレンスリバモア国立研究所(LLNL)
<関連情報>
- https://www.llnl.gov/article/53116/llnl-purdue-university-accelerate-discovery-medical-countermeasures-emerging-chemical-threats
- https://www.pnas.org/doi/10.1073/pnas.2512471122
A系化学兵器剤曝露に対する対策候補発見の加速化 Accelerating countermeasure candidate discovery for A-series chemical warfare agent exposure
Nicolás M. Morato, Katelyn E. Mason, Todd H. Corzett, Carlos A. Valdez, Teneile M. Alfaro, Saphon Hok, R. Graham Cooks
Proceedings of the National Academy of Sciences Published:July 17, 2025
DOI:https://doi.org/10.1073/pnas.2512471122
Significance
This study uses high-throughput mass spectrometry to address the urgent need for countermeasures against A-series chemical warfare agents (“Novichoks”). Using a surrogate- and label-free approach, we provide the first quantitative report on the in vitro potency of this group of agents as inhibitors of human acetylcholinesterase, demonstrating that they are on par with traditional agents. We also confirm the high stability of these enzyme-agent adducts while revealing the potential of bispyridinium-based oximes as scaffolds for new countermeasure candidates. By automating research with authentic toxic materials using ultrafast (>1 sample/s) mass spectrometry platforms, this work demonstrates a decentralized capability for safe, large-scale research on emerging chemical threats, enabling robust insights into their bioactivities and greatly accelerating the discovery of countermeasure candidates.
Abstract
The recent alleged use of A-series chemical warfare agents (CWAs) highlights the urgent need to better understand their inhibition of cholinesterase enzymes and the reported shortcomings of traditional oxime countermeasures. Here, using high-throughput (HT) mass spectrometry (MS) technologies, we characterized the largely unknown inhibition kinetics of A-series CWAs on human acetylcholinesterase (hAChE) and its reactivation by oximes, achieving label-free quantitation at rates of up to 7,000 reactions per hour. Our findings indicate i) A-series agents exhibit inhibitory potencies similar to traditional CWAs like sarin and VX, and ii) bipyridinium-based oximes can reactivate A-series-adducted hAChE in vitro, challenging prior reports on oxime efficacy. These results underscore the need for continued exploration of countermeasure candidates against A-series CWAs and demonstrate the potential of HT-MS for rapidly and safely characterizing emerging toxic chemicals.
