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

Zrinka Kovarik, Nikolina Maček Hrvat, Maja Katalinić, Rakesh K. Sit, Alexander Paradyse, Suzana Žunec, Kamil Musilek, Valery V. Fokin, Palmer Taylor, Zoran Radić

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1036-1044
Number of pages9
JournalChemical Research in Toxicology
Volume28
Issue number5
DOIs
Publication statusPublished - 18 May 2015
Externally publishedYes

Fingerprint

Soman
Oximes
Scavenging
Acetylcholinesterase
Blood
Aging of materials
Sarin
Dealkylation
Paraoxon
Butyrylcholinesterase
Antidotes
Molecular Models
Organophosphates
Angle of attack
Toxicity
asoxime chloride
Derivatives

ASJC Scopus subject areas

  • Toxicology

Cite this

Kovarik, Z., Maček Hrvat, N., Katalinić, M., Sit, R. K., Paradyse, A., Žunec, S., ... Radić, Z. (2015). Catalytic Soman Scavenging by the Y337A/F338A Acetylcholinesterase Mutant Assisted with Novel Site-Directed Aldoximes. Chemical Research in Toxicology, 28(5), 1036-1044. https://doi.org/10.1021/acs.chemrestox.5b00060

Catalytic Soman Scavenging by the Y337A/F338A Acetylcholinesterase Mutant Assisted with Novel Site-Directed Aldoximes. / Kovarik, Zrinka; Maček Hrvat, Nikolina; Katalinić, Maja; Sit, Rakesh K.; Paradyse, Alexander; Žunec, Suzana; Musilek, Kamil; Fokin, Valery V.; Taylor, Palmer; Radić, Zoran.

In: Chemical Research in Toxicology, Vol. 28, No. 5, 18.05.2015, p. 1036-1044.

Research output: Contribution to journalArticle

Kovarik, Z, Maček Hrvat, N, Katalinić, M, Sit, RK, Paradyse, A, Žunec, S, Musilek, K, Fokin, VV, Taylor, P & Radić, Z 2015, 'Catalytic Soman Scavenging by the Y337A/F338A Acetylcholinesterase Mutant Assisted with Novel Site-Directed Aldoximes', Chemical Research in Toxicology, vol. 28, no. 5, pp. 1036-1044. https://doi.org/10.1021/acs.chemrestox.5b00060
Kovarik, Zrinka ; Maček Hrvat, Nikolina ; Katalinić, Maja ; Sit, Rakesh K. ; Paradyse, Alexander ; Žunec, Suzana ; Musilek, Kamil ; Fokin, Valery V. ; Taylor, Palmer ; Radić, Zoran. / Catalytic Soman Scavenging by the Y337A/F338A Acetylcholinesterase Mutant Assisted with Novel Site-Directed Aldoximes. In: Chemical Research in Toxicology. 2015 ; Vol. 28, No. 5. pp. 1036-1044.
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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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