Discovery of New Classes of Compounds that Reactivate Acetylcholinesterase Inhibited by Organophosphates. Issue 15 (9th September 2015)

• Record Type: Journal Article
• Authors: Katz, Francine S.; Pecic, Stevan; Tran, Timothy H.; Trakht, Ilya; Schneider, Laura; Zhu, Zhengxiang; Ton‐That, Long; Luzac, Michal; Zlatanic, Viktor; Damera, Shivani; Macdonald, Joanne; Landry, Donald W.; Tong, Liang; Stojanovic, Milan N.
• Is Part Of: Chembiochem. Volume 16:Issue 15(2015)
• Page Start: 2205
• Page End: 2215
• Publication Date: 2015-09-09
• Subjects: Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201500348
• Languages: English
• ISSNs: 1439-4227

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>Acetylcholinesterase (AChE) that has been covalently inhibited by organophosphate compounds (OPCs), such as nerve agents and pesticides, has traditionally been reactivated by using nucleophilic oximes. There is, however, a clearly recognized need for new classes of compounds with the ability to reactivate inhibited AChE with improved in vivo efficacy. Here we describe our discovery of new functional groups—Mannich phenols and general bases—that are capable of reactivating OPC‐inhibited AChE more efficiently than standard oximes and we describe the cooperative mechanism by which these functionalities are delivered to the active site. These discoveries, supported by preliminary in vivo results and crystallographic data, significantly broaden the available approaches for reactivation of AChE.</p> </abstract>