Naslov
Efficient detoxification of soman, tabun, and VX by oxime assisted reactivation of acetylcholinesterase mutants

Autori
Kovarik, Zrinka ; Maček Hrvat, Nikolina ; Žunec, Suzana ; Katalinić, Maja ; Taylor, Palmer ; Radić, Zoran

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Journal of Neurochemistry, Vol.142(2), Special issue on Cholinergic Mechanisms / Guest Editor: Israel Silman, Associate Guest Editors: Pascale Marchot and Marco Prado - , 2017, 193-193

Skup
XVth International Symposium on Cholinergic Mechanisms

Mjesto i datum
Marseille, Francuska, 16.10.2016. - 20.10.2016

Vrsta sudjelovanja
Pozvano predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
endogenous BChE ; Y337A ; Y337A/F338A

Sažetak
Newly considered strategies in medical protection against nerve agents focus on the use of exogenously administered butyrylcholinesterase (BChE). The overall idea is to supplement endogenous BChE in combination with a specific oxime, to scavenge an organophosphate (OP) before it can reach and inhibit native acetylcholinesterase (AChE) in target tissues, thus helping organism detoxification from the excess OP. However, oxime antidotes commonly used to reactivate OP inhibited AChE are ineffective against soman and tabun, while the efficacy of the recommended nerve agent bioscavenger BChE is limited by strictly stoichiometric scavenging. Our previous research showed that AChE mutagenesis can enable aldoximes to substantially accelerate the reactivation of OP-enzyme conjugates, while dramatically slowing down rates of OP-conjugate dealkylation (aging). Herein we demonstrate through a combination of in silico, in vitro, ex vivo, and in vivo results, a feasible approach to the development of oxime assisted catalytic bioscavengers of soman, tabun and VX based on human AChE mutants modified at the choline binding site (Y337A and an aging resistant Y337A/F338A) in combination with its efficient reactivator. Ultimately, the oxime assisted catalytic scavenging of the nerve agents in mice improved therapeutic outcomes preventing lethality and resulted in a delayed onset of toxicity symptoms. Supported by the NIH (CounterACT Program, the NIH Office of the Director, and the National Institute of Neurological Disorders and Stroke, grant numbers U01 NS058046 and R21NS072086) and CSF (4307).

Izvorni jezik
Engleski

Znanstvena područja
Kemija

POVEZANOST RADA