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Pregled bibliografske jedinice broj: 994871

Counteracting tabun inhibition by reactivation by pyridinium aldoximes that interact with active center gorge mutants of acetylcholinesterase


Kovarik, Zrinka; Maček Hrvat, Nikolina; Kalisiak, Jarosław; Katalinić, Maja; Sit, Rakesh K.; Zorbaz, Tamara; Radić, Zoran; Fokin, Valery V.; Sharpless, K. Barry; Taylor, Palmer
Counteracting tabun inhibition by reactivation by pyridinium aldoximes that interact with active center gorge mutants of acetylcholinesterase // Toxicology and Applied Pharmacology, 372 (2019), 40-46 doi:10.1016/j.taap.2019.04.007 (međunarodna recenzija, članak, znanstveni)


Naslov
Counteracting tabun inhibition by reactivation by pyridinium aldoximes that interact with active center gorge mutants of acetylcholinesterase

Autori
Kovarik, Zrinka ; Maček Hrvat, Nikolina ; Kalisiak, Jarosław ; Katalinić, Maja ; Sit, Rakesh K. ; Zorbaz, Tamara ; Radić, Zoran ; Fokin, Valery V. ; Sharpless, K. Barry ; Taylor, Palmer

Izvornik
Toxicology and Applied Pharmacology (0041-008X) 372 (2019); 40-46

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Organophosphates ; acetylcholinesterase reactivation ; antidotes to nerve agents ; 2PAM ; bioscavengers ; phosphoramidates

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti, Javno zdravstvo i zdravstvena zaštita



POVEZANOST RADA


Projekt / tema
HRZZ-IP-2013-11-4307 - Dizajn, sinteza i evaluacija novih protuotrova kod trovanja živčanim bojnim otrovima i pesticidima (Zrinka Kovarik, )
HRZZ-IP-2018-01-7683 - Analiza interakcija butirilkolinesteraze s novim inhibitorima i reaktivatorima (Zrinka Kovarik, )

Ustanove
Institut za medicinska istraživanja i medicinu rada, Zagreb

Časopis indeksira:


  • Current Contents Connect (CCC)
  • Web of Science Core Collection (WoSCC)
    • Science Citation Index Expanded (SCI-EXP)
    • SCI-EXP, SSCI i/ili A&HCI
  • Scopus
  • MEDLINE


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