Kovarik_2019_Toxicol.Appl.Pharmacol_372_40

Reference

Title : Counteracting tabun inhibition by reactivation by pyridinium aldoximes that interact with active center gorge mutants of acetylcholinesterase - Kovarik_2019_Toxicol.Appl.Pharmacol_372_40
Author(s) : Kovarik Z , Macek Hrvat N , Kalisiak J , Katalinic M , Sit RK , Zorbaz T , Radic Z , Fokin VV , Sharpless KB , Taylor P
Ref : Toxicol Appl Pharmacol , 372 :40 , 2019
Abstract : Tabun represents the phosphoramidate class of organophosphates that are covalent inhibitors of acetylcholinesterase (AChE), an essential enzyme in neurotransmission. Currently used therapy in counteracting excessive cholinergic stimulation consists of a muscarinic antagonist (atropine) and an oxime reactivator of inhibited AChE, but the classical oximes are particularly ineffective in counteracting tabun exposure. In a recent publication (Kovarik et al., 2019), we showed that several oximes prepared by the Huisgen 1,3 dipolar cycloaddition and related precursors efficiently reactivate the tabun-AChE conjugate. Herein, we pursue the antidotal question further and examine a series of lead precursor molecules, along with triazole compounds, as reactivators of two AChE mutant enzymes. Such studies should reveal structural subtleties that reside within the architecture of the active center gorge of AChE and uncover intimate mechanisms of reactivation of alkylphosphate conjugates of AChE. The designated mutations appear to minimize steric constraints of the reactivating oximes within the impacted active center gorge. Indeed, after initial screening of the triazole oxime library and its precursors for the reactivation efficacy on Y337A and Y337A/F338A human AChE mutants, we found potentially active oxime-mutant enzyme pairs capable of degrading tabun in cycles of inhibition and reactivation. Surprisingly, the most sensitive ex vivo reactivation of mutant AChEs occurred with the alkylpyridinium aldoximes. Hence, although the use of mutant enzyme bio-scavengers in humans may be limited in practicality, bioscavenging and efficient neutralization of tabun itself or phosphoramidate mixtures of organophosphates might be achieved efficiently in vitro or ex vivo with these mutant AChE combinations.
ESTHER : Kovarik_2019_Toxicol.Appl.Pharmacol_372_40
PubMedSearch : Kovarik_2019_Toxicol.Appl.Pharmacol_372_40
PubMedID: 30978400
Gene_locus related to this paper: human-ACHE

Related information

Gene_locus related to this paper: human-ACHE

Citations formats

Kovarik Z, Macek Hrvat N, Kalisiak J, Katalinic M, Sit RK, Zorbaz T, Radic Z, Fokin VV, Sharpless KB, Taylor P (2019)
Counteracting tabun inhibition by reactivation by pyridinium aldoximes that interact with active center gorge mutants of acetylcholinesterase
Toxicol Appl Pharmacol 372 :40

Kovarik Z, Macek Hrvat N, Kalisiak J, Katalinic M, Sit RK, Zorbaz T, Radic Z, Fokin VV, Sharpless KB, Taylor P (2019)
Toxicol Appl Pharmacol 372 :40