Counteracting tabun inhibition by reactivation by pyridinium aldoximes that interact with active center gorge mutants of acetylcholinesterase (CROSBI ID 263321)
Prilog u časopisu | izvorni znanstveni rad | međunarodna recenzija
Podaci o odgovornosti
Kovarik, Zrinka ; Maček Hrvat, Nikolina ; Kalisiak, Jarosław ; Katalinić, Maja ; Sit, Rakesh K. ; Zorbaz, Tamara ; Radić, Zoran ; Fokin, Valery V. ; Sharpless, K. Barry ; Taylor, Palmer
engleski
Counteracting tabun inhibition by reactivation by pyridinium aldoximes that interact with active center gorge mutants of acetylcholinesterase
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 conjugates might be achieved with mutant AChE- oxime combinations.
organophosphates ; acetylcholinesterase reactivation ; antidotes to nerve agents ; 2PAM ; bioscavengers ; phosphoramidates
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Podaci o izdanju
372
2019.
40-46
objavljeno
0041-008X
1096-0333
10.1016/j.taap.2019.04.007
Povezanost rada
Javno zdravstvo i zdravstvena zaštita, Kemija, Temeljne medicinske znanosti