Journal
CHEMICAL RESEARCH IN TOXICOLOGY
Volume 28, Issue 5, Pages 1036-1044Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.chemrestox.5b00060
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Funding
- NIH [U01 NS058046, R21NS072086]
- Croatian Ministry of Science, Education and Sports Grant [022-0222148-2889]
- Croatian Science Foundation [4307]
- University of Hradec Kralove (long-term development plan)
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Exposure to the nerve agent soman is difficult to treat due to the rapid dealkylation of the soman-acetylcholinesterase (AChE) conjugate known as. aging. Oxime antidotes commonly used to reactivate organophosphate inhibited AChE ate ineffective against soman, while the efficacy of the recommended nerve agent bioscavenger butyrylcholinesterase is limited by strictly stoichiometric scavenging. To overcome this limitation, we tested ex vivo, in human blood, and in vivo, in soman exposed mice, the capacity of aging-resistant human AChE Mutant Y337A/F338A in combination with oxime HI-6 to act as a catalytic bioscavenger of soman. HI-6 was previously shown, in vitro to efficiently reactivate this mutant upon soman, as well as VX, cyclosarin, satin, and paraoxon, inhibition. We here demonstrate that ex vivo, in whole human blood, 1 mu M somari was detoxified within 30 min when supplemented with 04 mu M Y337A/F338A AChE and 100 yM HI-6. This combination was further tested in vivo, Catalytic scavenging of soman in mice improved the therapeutic outcome and resulted in the delayed onset of toxicity symptoms. Furthermore, in a preliminary in vitro screen we identified an even more efficacious oxime than HI-6, in a series of 42 pyridinium aldoximes, and 5 imidazole 2-aldoxime N-propylpyridinium derivatives. One of the later imidazole aldoximes, RS-170B, was a 2-3-fold more effective reactivator of Y337A/F338A AChE than HI-6 due to the smaller imidazole ring, as indicated by computational molecular models, that affords a more productive angle of nucleophilic attack.
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