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

Francine S Katz; Stevan Pecic; Timothy H Tran; Ilya Trakht; Laura Scheider; Zhengxiang Zhu; Long Ton-That; Michal Luzac; Viktor Zlatanic; Shivani Damera; Joanne Macdonald; Donald W Landry; Liang Tong; Milan N Stojanovic

doi:10.1002/cbic.201500348

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

Journal article

Open access

Peer reviewed

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

Francine S Katz, Stevan Pecic, Timothy H Tran, Ilya Trakht, Laura Scheider, Zhengxiang Zhu, Long Ton-That, Michal Luzac, Viktor Zlatanic, Shivani Damera, …

ChemBioChem, Vol.16(15), pp.2205-2215

2015

DOI: https://doi.org/10.1002/cbic.201500348

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Abstract

drug discovery

high-throughput screening

medicinal chemistry

neurological agents

structure-activity relationships

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.

Details

Title: Discovery of New Classes of Compounds that Reactivate Acetylcholinesterase Inhibited by Organophosphates
Authors: Francine S Katz (Author) - Columbia University Medical Centre, United States
Stevan Pecic (Author) - Columbia University Medical Centre, United States
Timothy H Tran (Author) - Columbia University, United States
Ilya Trakht (Author) - Columbia University Medical Centre, United States
Laura Scheider (Author) - Columbia University Medical Centre, United States
Zhengxiang Zhu (Author) - Columbia University Medical Centre, United States
Long Ton-That (Author) - Columbia University Medical Centre, United States
Michal Luzac (Author) - Columbia University Medical Centre, United States
Viktor Zlatanic (Author) - Columbia University Medical Centre, United States
Shivani Damera (Author) - Columbia University Medical Centre, United States
Joanne Macdonald (Author) - University of the Sunshine Coast - Faculty of Science, Health, Education and Engineering
Donald W Landry (Author) - Columbia University Medical Centre, United States
Liang Tong (Author) - Columbia University, United States
Milan N Stojanovic (Author) - Columbia University Medical Centre, United States
Publication details: ChemBioChem, Vol.16(15), pp.2205-2215
Publisher: Wiley - V C H Verlag GmbH & Co. KGaA
Date published: 2015
DOI: 10.1002/cbic.201500348
ISSN: 1439-4227
Copyright note: Copyright © 2015 The Author. This is the peer reviewed version of the following article: F. S. Katz, S. Pecic, T. H. Tran, I. Trakht, L. Schneider, Z. Zhu, L. Ton-That, M. Luzac, V. Zlatanic, S. Damera, J. Macdonald, D. W. Landry, L. Tong, M. N. Stojanovic, ChemBioChem 2015, 16, 2205, which has been published in final form at http://dx.doi.org/10.1002/cbic.201500348. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
Organisation Unit: School of Science and Engineering - Legacy; University of the Sunshine Coast, Queensland; School of Science, Technology and Engineering; Centre for Bioinnovation
Language: English
Record Identifier: 99449920802621
Output Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Web Of Science research areas: Biochemistry & Molecular Biology; Chemistry, Medicinal

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