title: Catalytic Soman Scavenging by the Y337A/F338A Acetylcholinesterase Mutant Assisted with Novel Site-Directed Aldoximes.
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.
authors.affiliation: †Institute for Medical Research and Occupational Health, Ksaverska cesta 2, HR-10000 Zagreb, Croatia.
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Kovarik
authors.affiliation: †Institute for Medical Research and Occupational Health, Ksaverska cesta 2, HR-10000 Zagreb, Croatia.
authors.forename: Nikolina
authors.initials: N
authors.lastname: Maček Hrvat
authors.affiliation: †Institute for Medical Research and Occupational Health, Ksaverska cesta 2, HR-10000 Zagreb, Croatia.
authors.forename: Maja
authors.initials: M
authors.lastname: Katalinić
authors.affiliation: ‡Skaggs Institute for Chemical Biology and Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Sit
authors.forename: Alexander
authors.initials: A
authors.lastname: Paradyse
authors.affiliation: †Institute for Medical Research and Occupational Health, Ksaverska cesta 2, HR-10000 Zagreb, Croatia.
authors.forename: Suzana
authors.initials: S
authors.lastname: Žunec
authors.affiliation: ∥Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 50003 Hradec Kralove, Czech Republic.
authors.forename: Kamil
authors.initials: K
authors.lastname: Musilek
authors.affiliation: ‡Skaggs Institute for Chemical Biology and Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States.
authors.forename: Valery V
authors.initials: VV
authors.lastname: Fokin
authors.forename: Palmer
authors.initials: P
authors.lastname: Taylor
authors.forename: Zoran
authors.initials: Z
authors.lastname: Radić
mesh_terms: D000110:Acetylcholinesterase / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D010091:Oximes / Q000494:pharmacology*; D017354:Point Mutation; D011726:Pyridinium Compounds / Q000494:pharmacology*; D012999:Soman / Q000633:toxicity*
chemical_list: D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010091:Oximes; D011726:Pyridinium Compounds; D012999:Soman; D000110:Acetylcholinesterase; C022870:asoxime chloride
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