Cholinesterases and oximes as pseudo-catalytic bioscavengers of nerve warfare agents

Maček Hrvat, Nikolina (2015) Cholinesterases and oximes as pseudo-catalytic bioscavengers of nerve warfare agents. Doctoral thesis, Faculty of Science > Department of Chemistry.

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Abstract

Organophosphates (OP) such as nerve agents (tabun, soman, VX) irreversibly inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The treatment in case of exposure to OP compounds includes the administration of the anticholinergic drug atropine and an oxime reactivator. Since this therapy has proven insufficient, today, among other solutions, pseudo-catalytic bioscavengers, enzymes designed with the aim to degrade OPs with turnover before it interacts with synaptic AChE, are investigated as prophylactics. We tested 17 oximes as reactivators of human AChE, BChE, Y337A and the Y337A/F338A mutant of AChE inhibited by tabun, VX and soman. The most effective oxime-enzyme couples identified were further tested ex vivo for degradation of tabun, VX or soman by oxime-enzyme assisted hydrolysis. It was shown that among the studied oximes there were those that in combination with the investigated enzymes could serve as pseudo-catalytic bioscavengers of tabun (oxime 1-hexyl-2-(hydroxyimino)methylpyridinium chloride (JAR288C) and Y337A mutant), VX (oxime HI-6 and Y337A/F338A mutant) and soman(oxime HI-6 and Y337A/F338A mutant). The tested oximes and AChE mutant pairs reactivated a high percentage of enzyme activity, achieving reactivation rate constants above0.2 min-1, oxime-mutant dissociation constants about 0.1 mol min-1 dm-3 and a rate of enzyme inhibition within the range of native AChE inhibition. These catalytic parameters represent the necessary criteria for oxime-enzyme induced OP degradation, i.e. for effective nerve agent pseudo-catalytic bioscavengers.

Item Type: Thesis (Doctoral thesis)
Keywords: acetylcholinesterase, acetylcholinesterase mutants, butyrylcholinesterase, organophosphates, reactivators
Supervisor: Kovarik, Zrinka
Date: 2015
Number of Pages: 111
Subjects: NATURAL SCIENCES > Chemistry
Divisions: Faculty of Science > Department of Chemistry
Depositing User: Branka Maravic
Date Deposited: 24 Apr 2015 10:34
Last Modified: 15 Jun 2015 13:29
URI: http://digre.pmf.unizg.hr/id/eprint/3886

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