Naslov
Converting butyrylcholinesterase from stoichiometric to catalytic bioscavenger

Autori
Radić Zoran ; Dale, Trevor ; Garcia, Edzna ; Zhang, Limin ; Kovarik, Zrinka ; Amitai, Gabriel ; Ajami, Dariush ; Rebek, Julius Jr. ; Taylor, Palmer

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

Izvornik
11th International Meeting on Cholinesterases, Kazan, Rusija, Book of Abstracts / Lushchekina, S. - : Kazan State University, 2012

Skup
11th International Meeting on Cholinesterases

Mjesto i datum
Kazan, Ruska Federacija, 04.06.2012. - 09.06.2012

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
nonpyridinium quaternary oximes; sarin; cyclosarin; VX; paraoxon; TD-6-209ex2

Sažetak
From a small, structurally directed library of quaternary ammonium oximes we identified reactivators with capacity to rapidly reactivate human butyrylcholinesterase (hBChE) covalently conjugated with nerve agents sarin, cyclosarin, VX and an organophosphate (OP) paraoxon, faster than the reference oxime reactivator 2PAM. Detailed reactivation kinetics of the lead oxime reactivator TD-6-209ex2 for OP-conjugated hBChE as well as for human acetylcholinesterase (hAChE) conjugates revealed the oxime preference for OP-hBChE reactivation largely because its very poor reversible binding to OP-hAChE conjugates (large Kox constants). Biphasic dependence of nucleophilic reactivity of TD-6-209ex2 on pH suggests formation of a nucleophile in addition to the oximate anion, with approximate pKa of 7.5 resulting in enhanced nucleophilic reactivation at physiological pH. Total cholinesterase activity of human blood supplemented with purified hBChE and exposed to excess OP concentrations recovered significantly upon addition of 100 uM TD-6-209ex2 within minutes. The recovery was faster than in the absence of hBChE indicating catalytic turnover of OP in blood. Mice pretreated with substoichiometric amounts of hBChE, exposed to paraoxon and treated therapeutically with 25 mg/kg TD-6-209ex2 were more resistant to intoxication than mice not pretreated with hBChE (respective protective indices were 10 and 14). Pretreatment of mice with a combination of hBChE and TD-6-209ex2, followed by TD-6-209ex2 therapy resulted in a protective index of 16-25. Enhancement of protective indices in the pretreatment by substoichiometric amounts of hBChE is indicative of catalytic turnover of OP assisted by oxime TD-6-209ex2.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

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