Reversal of tabun toxicity enabled by a triazole-annulated oxime library - reactivators of acetylcholinesterase

Kovarik, Zrinka; Kalisiak, Jarosław; Maček Hrvat, Nikolina; Katalinić, Maja; Zorbaz, Tamara; Žunec, Suzana; Green, Carol; Radić, Zoran; Fokin, Valery V.; Sharpless, Barry K.; Taylor, Palmer

doi:10.1002/chem.201805051

Pregled bibliografske jedinice broj: 957383

Reversal of tabun toxicity enabled by a triazole-annulated oxime library - reactivators of acetylcholinesterase

Kovarik, Zrinka; Kalisiak, Jarosław; Maček Hrvat, Nikolina; Katalinić, Maja; Zorbaz, Tamara; Žunec, Suzana; Green, Carol; Radić, Zoran; Fokin, Valery V.; Sharpless, Barry K.; Taylor, Palmer

Reversal of tabun toxicity enabled by a triazole-annulated oxime library - reactivators of acetylcholinesterase // Chemistry - A European Journal, 25 (2019), 16; 4100-4114 doi:10.1002/chem.201805051 (međunarodna recenzija, članak, znanstveni)

CROSBI ID: 957383 Za ispravke kontaktirajte CROSBI podršku putem web obrasca

Naslov
Reversal of tabun toxicity enabled by a triazole-annulated oxime library - reactivators of acetylcholinesterase

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

Izvornik
Chemistry - A European Journal (0947-6539) 25 (2019), 16; 4100-4114

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

Ključne riječi
nerve agents, acetylcholinesterase, organophosphate antidotes, 2-PAM, triazole-linked oximes

Sažetak
Acetylcholinesterase (AChE), an enzyme that degrades the neurotransmitter acetylcholine, when covalently inhibited by organophosphorus compounds (OPs), such as nerve agents and pesticides, can be reactivated by oximes. However, tabun remains among the most dangerous nerve agents due to the low reactivation efficacy of standard pyridinium aldoxime antidotes. Therefore, finding an optimal reactivator for prophylaxis against tabun toxicity and for post-exposure treatment is a continued challenge. In this study, we analyzed the reactivation potency of 111 novel nucleophilic oximes mostly synthesized using the CuAAC triazole ligation between alkyne and azide building blocks. We identified several oximes with significantly improved in vitro reactivating potential for tabun-inhibited human AChE, and in vivo antidotal efficacies in tabun-exposed mice. Our findings offer a significantly improved platform for further development of antidotes and scavengers directed against tabun and related phosphoramidate exposures, such as the Novichok compounds.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Javno zdravstvo i zdravstvena zaštita, Farmacija

POVEZANOST RADA

Projekti:
HRZZ-IP-2013-11-4307 - Dizajn, sinteza i evaluacija novih protuotrova kod trovanja živčanim bojnim otrovima i pesticidima (CHOLINESTERASE) (Kovarik, Zrinka, HRZZ - 2013-11) ( CroRIS)

Ustanove:
Institut za medicinska istraživanja i medicinu rada, Zagreb

Profili:

Suzana Žunec (autor)