HI-6 assisted catalytic scavenging of VX by acetylcholinesterase choline binding site mutants.

Abstract	The high toxicity of organophosphorus compounds originates from covalent inhibition of acetylcholinesterase (AChE), an essential enzyme in cholinergic neurotransmission. Poisonings that lead to life-threatening toxic manifestations require immediate treatment that combines administration of anticholinergic drugs and an aldoxime as a reactivator of AChE. An alternative approach to reduce the in vivo toxicity of OPs focuses on the use of bioscavengers against the parent organophosphate. Our previous research showed that AChE mutagenesis can enable aldoximes to substantially accelerate the reactivation of OP-enzyme conjugates, while dramatically slowing down rates of OP-conjugate dealkylation (aging). Herein, we demonstrate an efficient HI-6-assisted VX detoxification, both ex vivo in human blood and in vivo in mice by hAChE mutants modified at the choline binding site (Y337A and Y337A/F338A). The catalytic scavenging of VX in mice improved therapeutic outcomes preventing lethality and resulted in a delayed onset of toxicity symptoms.
Authors	Nikolina Maček Hrvat, Suzana Žunec, Palmer Taylor, Zoran Radić, Zrinka Kovarik
Journal	Chemico-biological interactions (Chem Biol Interact) Vol. 259 Issue Pt B Pg. 148-153 (Nov 25 2016) ISSN: 1872-7786 [Electronic] Ireland
PMID	27083141 (Publication Type: Journal Article)
Copyright	Copyright Â© 2016 Elsevier Ireland Ltd. All rights reserved.
Chemical References	Cholinesterase Inhibitors Cholinesterase Reactivators Organothiophosphorus Compounds Oximes Pyridinium Compounds Recombinant Proteins VX Acetylcholinesterase asoxime chloride
Topics	Acetylcholinesterase (chemistry, genetics, metabolism) Animals Binding Sites Cholinesterase Inhibitors (chemistry, metabolism, poisoning) Cholinesterase Reactivators (chemistry, metabolism, therapeutic use) Humans Kinetics Male Mice Mutagenesis, Site-Directed Organophosphate Poisoning (drug therapy, mortality, veterinary) Organothiophosphorus Compounds (chemistry, metabolism, poisoning) Oximes (chemistry, metabolism, therapeutic use) Pyridinium Compounds (chemistry, metabolism, therapeutic use) Recombinant Proteins (biosynthesis, chemistry) Survival Rate

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