Discovery of New Classes of Compounds that Reactivate Acetylcholinesterase Inhibited by Organophosphates

Journal Article · Wed Sep 09 04:00:00 EDT 2015 · ChemBioChem: a European journal of chemical biology

DOI:https://doi.org/10.1002/cbic.201500348· OSTI ID:1354335

Katz, Francine S. ^[1]; Pecic, Stevan ^[1]; Tran, Timothy H. ^[2]; Trakht, Ilya ^[1]; Schneider, Laura ^[1]; Zhu, Zhengxiang ^[1]; Ton-That, Long ^[1]; Luzac, Michal ^[1]; Zlatanic, Viktor ^[1]; Damera, Shivani ^[1]; Macdonald, Joanne ^[3]; Landry, Donald W. ^[1]; Tong, Liang ^[2]; Stojanovic, Milan N. ^[4]

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1. Department of Medicine/Division of Experimental Therapeutics, Columbia University Medical Center, 630 W. 168th Street New York NY 10032 USA
2. Department of Biological Sciences, Columbia University, 1212 Amsterdam Avenue New York NY 10027 USA
3. Department of Medicine/Division of Experimental Therapeutics, Columbia University Medical Center, 630 W. 168th Street New York NY 10032 USA; Genecology Research Centre, Inflammation and Healing Research Cluster, School of Science and Engineering, University of the Sunshine Coast, 90 Sippy Downs Drive Sippy Downs QLD 4556 Australia
4. Department of Medicine/Division of Experimental Therapeutics, Columbia University Medical Center, 630 W. 168th Street New York NY 10032 USA; Departments of Biomedical Engineering and Systems Biology, Columbia University, 630 W. 168th street New York NY 10032 USA

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.

• Research Organization: Brookhaven National Laboratory (BNL), Upton, NY (United States)
• Sponsoring Organization: USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
• OSTI ID: 1354335
• Report Number(s): BNL--112851-2016-JA
• Journal Information: ChemBioChem: a European journal of chemical biology, Journal Name: ChemBioChem: a European journal of chemical biology Journal Issue: 15 Vol. 16; ISSN 1439-4227
• Publisher: ChemPubSoc Europe
• Country of Publication: United States
• Language: English

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY