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
- Brian P. Mayer
2025-07-17
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 ( h AChE) 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 h AChE 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.