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Phosphonylated Acetylcholinesterase: Probing the Mechanism of a Small Molecule Reactivator
Author(s) -
Cadieux C Linn,
Wang Haoyu,
Zhang Yuchen,
Koenig Jeffrey,
Shih TsungMing,
McDonough John,
Koh John,
Cerasoli Douglas
Publication year - 2015
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.29.1_supplement.721.7
Subject(s) - nerve agent , sarin , tabun , acetylcholinesterase , soman , chemistry , pralidoxime , pharmacology , oxime , stereochemistry , aché , acetylcholine , biophysics , biochemistry , enzyme , medicine , biology
Currently fielded treatments for nerve agent intoxication include atropine, an acetylcholine receptor antagonist, and pralidoxime (2PAM), a small molecule reactivator of acetylcholinesterase (AChE). 2PAM reactivates nerve agent‐inhibited (NA‐)AChE via direct nucleophilic attack by the oxime moiety on the phosphorus center of the bound nerve agent. Due to a permanently charged pyridinium motif, 2PAM is not thought to cross the blood brain barrier and therefore cannot act directly in the neuronal junctions of the brain. In this study, a non‐permanently charged, non‐oxime molecule initially identified using pesticide‐inhibited AChE was tested for reactivation potential against NA‐AChE. The inhibitory and reactivation potentials of the molecule were determined with native AChE and AChE inhibited with tabun, sarin, soman, cyclosarin, VX, or VR and then compared to those of 2PAM. Then, several structural analogues of the candidate were used to probe the reactivation mechanism of the molecule. Additionally, the experimental condition under which reactivation was performed was altered in an attempt to determine the active form of the molecule. Finally, guinea pigs were used to examine the protective efficacy of the compound after exposure to sarin. Together, the results of both in vitro and in vivo testing will inform the design of future NA‐AChE small molecule reactivators.
This research was supported by the Defense Threat Reduction Agency ‐Joint Science Technology Office, Medical S&T Division.