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Catalytic soman scavenging by the Y337A/F338A acetylcholinesterase mutant assisted with novel site-directed aldoximes

Academic Article
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Overview

authors

  • Kovarik, Z.
  • Hrvat, N. M.
  • Katalinic, M.
  • Sit, R. K.
  • Paradyse, A.
  • Zunec, S.
  • Musilek, K.
  • Fokin, Valery
  • Taylor, P.
  • Radic, Z.

publication date

  • May 2015

journal

  • Chemical Research in Toxicology  Journal

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.

subject areas

  • Acetylcholinesterase
  • Animals
  • Chemical Warfare Agents
  • Cholinesterase Inhibitors
  • Cholinesterase Reactivators
  • Humans
  • Mice
  • Models, Molecular
  • Oximes
  • Point Mutation
  • Pyridinium Compounds
  • Soman
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Identity

PubMed Central ID

  • PMC4791098

International Standard Serial Number (ISSN)

  • 0893-228X

Digital Object Identifier (DOI)

  • 10.1021/acs.chemrestox.5b00060

PubMed ID

  • 25835984
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Additional Document Info

start page

  • 1036

end page

  • 1044

volume

  • 28

issue

  • 5

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