title: A new post-intoxication treatment of paraoxon and parathion poisonings using an evolved PON1 variant and recombinant GOT1.
abstract: Organophosphate (OP) based pesticides are highly toxic compounds that are still widely used in agriculture around the world. According to World Health Organization (WHO) data, it is estimated that between 250,000 and 370,000 deaths occur yearly around the globe as a result of acute intoxications by pesticides. Currently available antidotal drug treatments of severe OP intoxications are symptomatic, do not reduce the level of intoxicating OP in the body and have limited ability to prevent long-term brain damage. Pesticide poisonings present a special therapeutic challenge since in many cases, such as with parathion, their toxicity stems from their metabolites that inhibit the essential enzyme acetylcholinesterase. Our goal is to develop a new treatment strategy for parathion intoxication by combining a catalytic bioscavenger that rapidly degrades the intoxicating parathion-metabolite (paraoxon) in the blood, with a glutamate bioscavenger that reduces the elevated concentration of extracellular glutamate in the brain following OP intoxication. We report on the development of a novel catalytic bioscavenger by directed evolution of serum paraoxonase 1 (PON1) that effectively detoxifies paraoxon in-vivo. We also report preliminary results regarding the utilization of this PON1 variant together with a recombinant human enzyme glutamate oxaloacetate transaminase 1 (rGOT1), suggesting that a dual PON-GOT treatment may increase survival and recovery from parathion and paraoxon intoxications.
authors.affiliation: Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: moshe.goldsmith@weizmann.ac.il.
authors.forename: Moshe
authors.initials: M
authors.lastname: Goldsmith
authors.affiliation: Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel; Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yacov
authors.initials: Y
authors.lastname: Ashani
authors.affiliation: Science in Action Ltd., Ness Ziona, Israel.
authors.forename: Raanan
authors.initials: R
authors.lastname: Margalit
authors.affiliation: Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Abraham
authors.initials: A
authors.lastname: Nyska
authors.affiliation: Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Mirelman
authors.affiliation: Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Dan S
authors.initials: DS
authors.lastname: Tawfik
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood; D000818:Animals; D043303:Aryldialkylphosphatase / Q000378:metabolism*; D024443:Aspartate Aminotransferase, Cytoplasmic / Q000097:blood / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000473:pathology; D019020:Directed Molecular Evolution; D006801:Humans; D007700:Kinetics; D008297:Male; D062105:Molecular Docking Simulation; D050505:Mutant Proteins / Q000378:metabolism*; D010261:Paraoxon / Q000633:toxicity*; D010278:Parathion / Q000633:toxicity*; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism*; D013997:Time Factors
chemical_list: D050505:Mutant Proteins; D011994:Recombinant Proteins; D010278:Parathion; D024443:Aspartate Aminotransferase, Cytoplasmic; D000110:Acetylcholinesterase; D043303:Aryldialkylphosphatase; D010261:Paraoxon
keywords: Bioscavenger; Glutamate oxaloacetate transaminase 1; Intoxication; Organophosphates; Pesticides; Serum paraoxonase 1