Naslov
In vitro screening of acetylcholinesterase reactivating potency and oxime assisted organophosphate hydrolysis for a library of novel oxime reactivators synthesized by "click-chemistry"

Autori
Radić, Zoran ; Kalisiak, Jaroslaw ; Zhang, Limin ; Kovarik, Zrinka ; Čalić, Maja ; Amitai, Gabi ; Fokin, Valery V. ; Sharpless, Barry K. ; Taylor Palmer

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

Izvornik
The FASEB Journal, Vol.22., Experimental Biology 2008: "Today’ s Research: Tomorrow’ s Health" / - , 2008

Skup
Experimental Biology 2008: "Today’ s Research: Tomorrow’ s Health"

Mjesto i datum
San Diego (CA), Sjedinjene Američke Države, 05.04.2008. - 09.04.2008

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
oximes; reactivativation; VX; tabun; human acetylcholinesterase; mutants

Sažetak
Organophosphorus (OP) pesticides and nerve warfare agents stoichiometrically inactivate acetylcholinesterase (AChE ; EC 3.1.1.7) by phosphylation of the active serine 203. Catalytic activity of the covalently inhibited AChE can be effectively reclaimed only by nucleophiles stronger than water. In this study we analyzed reactivating potency of close to 100 novel oximes synthesized using [3+2] cycloaddition between alkyne and azide building blocks, the "Click reaction". Human AChE (hAChE) covalent adducts resulting from inhibition by nerve agents soman, sarin, cyclosarin, VX and tabun and pesticide derived paraoxon were used for reactivation experiments. We were able to identify several oximes with significantly improved reactivating efficacy against larger spectrum of offending OPs. We furthermore measured rates of hydrolysis of fluorescent derivatives of nerve agents soman, sarin, cyclosarin and VX assisted by oxime reactivators, for the wt AChE and Tyr337Ala mutant of hAChE, and found that in the presence of selected oximes rates of OP hydrolysis increased up to forty times with wt AChE and more with the Tyr337Ala hAChE mutant.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti

POVEZANOST RADA