Development of a CNS-permeable reactivator for nerve agent exposure: an iterative, multi-disciplinary approach

Abstract Nerve agents have experienced a resurgence in recent times with their use against civilian targets during the attacks in Syria (2012), the poisoning of Sergei and Yulia Skripal in the United Kingdom (2018) and Alexei Navalny in Russia (2020), strongly renewing the importance of antidote dev...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Brian J. Bennion, Michael A. Malfatti, Nicholas A. Be, Heather A. Enright, Saphon Hok, C. Linn Cadieux, Timothy S. Carpenter, Victoria Lao, Edward A. Kuhn, M. Windy McNerney, Felice C. Lightstone, Tuan H. Nguyen, Carlos A. Valdez
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f1620f48e97e419eb3cf95836925d7b8
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:f1620f48e97e419eb3cf95836925d7b8
record_format	dspace
spelling	oai:doaj.org-article:f1620f48e97e419eb3cf95836925d7b82021-12-02T16:23:42ZDevelopment of a CNS-permeable reactivator for nerve agent exposure: an iterative, multi-disciplinary approach10.1038/s41598-021-94963-22045-2322https://doaj.org/article/f1620f48e97e419eb3cf95836925d7b82021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-94963-2https://doaj.org/toc/2045-2322Abstract Nerve agents have experienced a resurgence in recent times with their use against civilian targets during the attacks in Syria (2012), the poisoning of Sergei and Yulia Skripal in the United Kingdom (2018) and Alexei Navalny in Russia (2020), strongly renewing the importance of antidote development against these lethal substances. The current standard treatment against their effects relies on the use of small molecule-based oximes that can efficiently restore acetylcholinesterase (AChE) activity. Despite their efficacy in reactivating AChE, the action of drugs like 2-pralidoxime (2-PAM) is primarily limited to the peripheral nervous system (PNS) and, thus, provides no significant protection to the central nervous system (CNS). This lack of action in the CNS stems from their ionic nature that, on one end makes them very powerful reactivators and on the other renders them ineffective at crossing the Blood Brain Barrier (BBB) to reach the CNS. In this report, we describe the use of an iterative approach composed of parallel chemical and in silico syntheses, computational modeling, and a battery of detailed in vitro and in vivo assays that resulted in the identification of a promising, novel CNS-permeable oxime reactivator. Additional experiments to determine acute and chronic toxicity are ongoing.Brian J. BennionMichael A. MalfattiNicholas A. BeHeather A. EnrightSaphon HokC. Linn CadieuxTimothy S. CarpenterVictoria LaoEdward A. KuhnM. Windy McNerneyFelice C. LightstoneTuan H. NguyenCarlos A. ValdezNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Brian J. Bennion Michael A. Malfatti Nicholas A. Be Heather A. Enright Saphon Hok C. Linn Cadieux Timothy S. Carpenter Victoria Lao Edward A. Kuhn M. Windy McNerney Felice C. Lightstone Tuan H. Nguyen Carlos A. Valdez Development of a CNS-permeable reactivator for nerve agent exposure: an iterative, multi-disciplinary approach
description	Abstract Nerve agents have experienced a resurgence in recent times with their use against civilian targets during the attacks in Syria (2012), the poisoning of Sergei and Yulia Skripal in the United Kingdom (2018) and Alexei Navalny in Russia (2020), strongly renewing the importance of antidote development against these lethal substances. The current standard treatment against their effects relies on the use of small molecule-based oximes that can efficiently restore acetylcholinesterase (AChE) activity. Despite their efficacy in reactivating AChE, the action of drugs like 2-pralidoxime (2-PAM) is primarily limited to the peripheral nervous system (PNS) and, thus, provides no significant protection to the central nervous system (CNS). This lack of action in the CNS stems from their ionic nature that, on one end makes them very powerful reactivators and on the other renders them ineffective at crossing the Blood Brain Barrier (BBB) to reach the CNS. In this report, we describe the use of an iterative approach composed of parallel chemical and in silico syntheses, computational modeling, and a battery of detailed in vitro and in vivo assays that resulted in the identification of a promising, novel CNS-permeable oxime reactivator. Additional experiments to determine acute and chronic toxicity are ongoing.
format	article
author	Brian J. Bennion Michael A. Malfatti Nicholas A. Be Heather A. Enright Saphon Hok C. Linn Cadieux Timothy S. Carpenter Victoria Lao Edward A. Kuhn M. Windy McNerney Felice C. Lightstone Tuan H. Nguyen Carlos A. Valdez
author_facet	Brian J. Bennion Michael A. Malfatti Nicholas A. Be Heather A. Enright Saphon Hok C. Linn Cadieux Timothy S. Carpenter Victoria Lao Edward A. Kuhn M. Windy McNerney Felice C. Lightstone Tuan H. Nguyen Carlos A. Valdez
author_sort	Brian J. Bennion
title	Development of a CNS-permeable reactivator for nerve agent exposure: an iterative, multi-disciplinary approach
title_short	Development of a CNS-permeable reactivator for nerve agent exposure: an iterative, multi-disciplinary approach
title_full	Development of a CNS-permeable reactivator for nerve agent exposure: an iterative, multi-disciplinary approach
title_fullStr	Development of a CNS-permeable reactivator for nerve agent exposure: an iterative, multi-disciplinary approach
title_full_unstemmed	Development of a CNS-permeable reactivator for nerve agent exposure: an iterative, multi-disciplinary approach
title_sort	development of a cns-permeable reactivator for nerve agent exposure: an iterative, multi-disciplinary approach
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f1620f48e97e419eb3cf95836925d7b8
work_keys_str_mv	AT brianjbennion developmentofacnspermeablereactivatorfornerveagentexposureaniterativemultidisciplinaryapproach AT michaelamalfatti developmentofacnspermeablereactivatorfornerveagentexposureaniterativemultidisciplinaryapproach AT nicholasabe developmentofacnspermeablereactivatorfornerveagentexposureaniterativemultidisciplinaryapproach AT heatheraenright developmentofacnspermeablereactivatorfornerveagentexposureaniterativemultidisciplinaryapproach AT saphonhok developmentofacnspermeablereactivatorfornerveagentexposureaniterativemultidisciplinaryapproach AT clinncadieux developmentofacnspermeablereactivatorfornerveagentexposureaniterativemultidisciplinaryapproach AT timothyscarpenter developmentofacnspermeablereactivatorfornerveagentexposureaniterativemultidisciplinaryapproach AT victorialao developmentofacnspermeablereactivatorfornerveagentexposureaniterativemultidisciplinaryapproach AT edwardakuhn developmentofacnspermeablereactivatorfornerveagentexposureaniterativemultidisciplinaryapproach AT mwindymcnerney developmentofacnspermeablereactivatorfornerveagentexposureaniterativemultidisciplinaryapproach AT feliceclightstone developmentofacnspermeablereactivatorfornerveagentexposureaniterativemultidisciplinaryapproach AT tuanhnguyen developmentofacnspermeablereactivatorfornerveagentexposureaniterativemultidisciplinaryapproach AT carlosavaldez developmentofacnspermeablereactivatorfornerveagentexposureaniterativemultidisciplinaryapproach
_version_	1718384145960271872

Development of a CNS-permeable reactivator for nerve agent exposure: an iterative, multi-disciplinary approach

Ejemplares similares