Journal article
New Therapeutic Approaches and Novel Alternatives for Organophosphate Toxicity
Toxicology Letters, Vol.291, pp.1-10
2018
Abstract
Organophosphate compounds (OPCs) are commonly used as pesticides and were developed as nerve agents for chemical warfare. Exposure to OPCs results in toxicity due to their covalent binding and inhibition of acetylcholinesterase (AChE). Treatment for toxicity due to OPC exposure has been largely focused on the reactivation of AChE by oxime-based compounds via direct nucleophilic attack on the phosphorous center. However, due to the disadvantages to existing oxime-based reactivators for treatment of OPC poisoning, we considered non-oxime mechanisms of reactivation. A high throughput screen of compound libraries was performed to discover previously unidentified reactivation compounds, followed by studies on their analogs. In the process, we discovered multiple non-oxime classes of compounds, the most robust of which we have already reported [1]. Herein, we report other classes of compounds we identified in our screen that are efficient at reactivation. During biochemical characterization, we also found some compounds with other activities that may inspire novel therapeutic approaches to OPC toxicity. Specifically, we found compounds that [1] increase the rate of substrate hydrolysis by AChE and, [2] protect the enzyme from inhibition by OPC. Further, we discovered that a subset of reactivator compounds recover activity from both AChE and the related enzyme butyrylcholinesterase (BuChE). We now report these compounds, their activities and discuss how each relates to therapeutic approaches that would provide alternatives to traditional oxime-based reactivation.
Details
- Title
- New Therapeutic Approaches and Novel Alternatives for Organophosphate Toxicity
- Authors
- Francine S Katz (Author) - Columbia University, United StatesStevan Pecic (Author) - Columbia University, United StatesLaura Schneider (Author) - Columbia University, United StatesZhengxiang Zhu (Author) - Columbia University, United StatesAshley Hastings (Author) - Columbia University, United StatesMichal Luzac (Author) - Columbia University, United StatesJoanne Macdonald (Author) - University of the Sunshine Coast - Faculty of Science, Health, Education and EngineeringDonald W Landry (Author) - Columbia University, United StatesMilan N Stojanovic (Author) - Columbia University, United States
- Publication details
- Toxicology Letters, Vol.291, pp.1-10
- Publisher
- Elsevier Ireland Ltd.
- Date published
- 2018
- DOI
- 10.1016/j.toxlet.2018.03.028
- ISSN
- 0378-4274; 0378-4274
- Copyright note
- Copyright © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
- 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
- 99450670102621
- Output Type
- Journal article
- Research Statement
- false
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- Domestic collaboration
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- Toxicology
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