title: 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.affiliation: Institute for Medical Research and Occupational Health, Zagreb, Croatia.
authors.forename: Nikolina
authors.initials: N
authors.lastname: Maček Hrvat
authors.affiliation: Institute for Medical Research and Occupational Health, Zagreb, Croatia.
authors.forename: Suzana
authors.initials: S
authors.lastname: Žunec
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093-0650, USA.
authors.forename: Palmer
authors.initials: P
authors.lastname: Taylor
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093-0650, USA.
authors.forename: Zoran
authors.initials: Z
authors.lastname: Radić
authors.affiliation: Institute for Medical Research and Occupational Health, Zagreb, Croatia. Electronic address: zkovarik@imi.hr.
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Kovarik
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000506:poisoning; D002801:Cholinesterase Reactivators / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D016297:Mutagenesis, Site-Directed; D062025:Organophosphate Poisoning / Q000188:drug therapy / Q000401:mortality / Q000662:veterinary; D009946:Organothiophosphorus Compounds / Q000737:chemistry / Q000378:metabolism* / Q000506:poisoning; D010091:Oximes / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D011726:Pyridinium Compounds / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry; D015996:Survival Rate
chemical_list: D000110:Acetylcholinesterase; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D009946:Organothiophosphorus Compounds; D010091:Oximes; D011726:Pyridinium Compounds; D011994:Recombinant Proteins; C009680:VX-agent; C022870:asoxime chloride
keywords: 2-PAM; Antidotes; Cholinesterase; Nerve agents; Organophosphates; Oximes; Reactivation