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In vitro screening of acetylcholinesterase reactivating potency and oxime assisted organophosphate hydrolysis for a library of novel oxime reactivators synthesized by “click‐chemistry”.
Author(s) -
Radic Zoran,
Kalisiak Jaroslaw,
Zhang Limin,
Kovarik Zrinka,
Calic Maja,
Amitai Gabi,
Fokin Valery V,
Sharpless Barry K,
Taylor Palmer
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.717.7
Subject(s) - nerve agent , sarin , chemistry , oxime , tabun , soman , acetylcholinesterase , paraoxon , organophosphate , butyrylcholinesterase , stereochemistry , medicinal chemistry , biochemistry , aché , enzyme , pesticide , agronomy , biology
Organophosphorus (OP) pesticides and nerve warfare agents stoichiometrically inactivate acetylcholinesterase (AChE; EC ) 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.