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

Chem Biol Interact. 2016 Nov 25;259(Pt B):148-153. doi: 10.1016/j.cbi.2016.04.023. Epub 2016 Apr 12.


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.

Keywords: 2-PAM; Antidotes; Cholinesterase; Nerve agents; Organophosphates; Oximes; Reactivation.

MeSH terms

  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / genetics
  • Acetylcholinesterase / metabolism*
  • Animals
  • Binding Sites
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / metabolism*
  • Cholinesterase Inhibitors / poisoning
  • Cholinesterase Reactivators / chemistry
  • Cholinesterase Reactivators / metabolism*
  • Cholinesterase Reactivators / therapeutic use
  • Humans
  • Kinetics
  • Male
  • Mice
  • Mutagenesis, Site-Directed
  • Organophosphate Poisoning / drug therapy
  • Organophosphate Poisoning / mortality
  • Organophosphate Poisoning / veterinary
  • Organothiophosphorus Compounds / chemistry
  • Organothiophosphorus Compounds / metabolism*
  • Organothiophosphorus Compounds / poisoning
  • Oximes / chemistry
  • Oximes / metabolism*
  • Oximes / therapeutic use
  • Pyridinium Compounds / chemistry
  • Pyridinium Compounds / metabolism*
  • Pyridinium Compounds / therapeutic use
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / chemistry
  • Survival Rate


  • Cholinesterase Inhibitors
  • Cholinesterase Reactivators
  • Organothiophosphorus Compounds
  • Oximes
  • Pyridinium Compounds
  • Recombinant Proteins
  • VX
  • Acetylcholinesterase
  • asoxime chloride