Development of a CNS-permeable reactivator for nerve agent exposure: an iterative, multi-disciplinary approach
| العنوان: | Development of a CNS-permeable reactivator for nerve agent exposure: an iterative, multi-disciplinary approach |
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| المؤلفون: | Tuan H. Nguyen, Brian J. Bennion, Heather A. Enright, C Linn Cadieux, Felice C. Lightstone, Nicholas A. Be, Michael A. Malfatti, M. Windy McNerney, Victoria Lao, Timothy S. Carpenter, Saphon Hok, Edward A. Kuhn, Carlos A. Valdez |
| المصدر: | Scientific Reports Scientific Reports, Vol 11, Iss 1, Pp 1-16 (2021) |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Central Nervous System, Male, medicine.medical_treatment, Science, Central nervous system, Guinea Pigs, Blood–brain barrier, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, In vivo, medicine, Animals, Antidote, 030304 developmental biology, Nerve agent, 0303 health sciences, Multidisciplinary, Pralidoxime Compounds, Multi disciplinary, business.industry, Drug discovery, Acetylcholinesterase, Computational biology and bioinformatics, Chemistry, medicine.anatomical_structure, chemistry, Blood-Brain Barrier, Peripheral nervous system, Medicine, business, Neuroscience, 030217 neurology & neurosurgery, medicine.drug |
| الوصف: | 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. |
| تدمد: | 2045-2322 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::db93f7d2c1a7cfb25a3c684190fb3e04 https://pubmed.ncbi.nlm.nih.gov/34330964 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....db93f7d2c1a7cfb25a3c684190fb3e04 |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 20452322 |
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