Catalytic Soman Scavenging by the Y337A/F338A Acetylcholinesterase Mutant Assisted with Novel Site-Directed Aldoximes.

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  • Additional Information
    • Source:
      Publisher: American Chemical Society Country of Publication: United States NLM ID: 8807448 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-5010 (Electronic) Linking ISSN: 0893228X NLM ISO Abbreviation: Chem Res Toxicol Subsets: MEDLINE
    • Publication Information:
      Publication: Washington Dc : American Chemical Society
      Original Publication: Washington, DC : American Chemical Society, c1988-
    • Subject Terms:
      Acetylcholinesterase/*genetics ; Acetylcholinesterase/*pharmacology ; Chemical Warfare Agents/*toxicity ; Cholinesterase Inhibitors/*toxicity ; Cholinesterase Reactivators/*pharmacology ; Oximes/*pharmacology ; Pyridinium Compounds/*pharmacology ; Soman/*toxicity; Acetylcholinesterase/metabolism ; Animals ; Humans ; Mice ; Models, Molecular ; Point Mutation
    • Abstract:
      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 are 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, sarin, and paraoxon, inhibition. We here demonstrate that ex vivo, in whole human blood, 1 μM soman was detoxified within 30 min when supplemented with 0.5 μM Y337A/F338A AChE and 100 μM 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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    • Grant Information:
      R21 NS072086 United States NS NINDS NIH HHS; U01 NS058046 United States NS NINDS NIH HHS; U01 NS083451 United States NS NINDS NIH HHS; R21NS072086 United States NS NINDS NIH HHS
    • Accession Number:
      0 (Chemical Warfare Agents)
      0 (Cholinesterase Inhibitors)
      0 (Cholinesterase Reactivators)
      0 (Oximes)
      0 (Pyridinium Compounds)
      96-64-0 (Soman)
      EC 3.1.1.7 (Acetylcholinesterase)
      HUV88P6SJS (asoxime chloride)
    • Publication Date:
      Date Created: 20150404 Date Completed: 20160210 Latest Revision: 20240525
    • Publication Date:
      20240525
    • Accession Number:
      PMC4791098
    • Accession Number:
      10.1021/acs.chemrestox.5b00060
    • Accession Number:
      25835984