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

Bennion, Brian J.; Malfatti, Michael A.; Be, Nicholas A.; Enright, Heather A.; Hok, Saphon; Cadieux, C. Linn; Carpenter, Timothy S.; Lao, Victoria; Kuhn, Edward A.; McNerney, M. Windy; Lightstone, Felice C.; Nguyen, Tuan H.; Valdez, Carlos A.

doi:10.1038/s41598-021-94963-2

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

Journal Article · 29 July 2021 · Scientific Reports

DOI: https://doi.org/10.1038/s41598-021-94963-2 · OSTI ID:1823222

Bennion, Brian J. ^[1]; Malfatti, Michael A. ^[1]; Be, Nicholas A. ^[1]; Enright, Heather A. ^[1]; Hok, Saphon ^[1]; Cadieux, C. Linn ^[2]; Carpenter, Timothy S. ^[1]; Lao, Victoria ^[1]; Kuhn, Edward A. ^[1]; McNerney, M. Windy ^[3]; Lightstone, Felice C. ^[1]; Nguyen, Tuan H. ^[1]; Valdez, Carlos A. ^[1]

Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
United States Army Medical Research Institute of Chemical Defense, Aberdeen, MD (United States)
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Mental Illness Research, Education and Clinical Center, Palo Alto, CA (United States); Stanford University School of Medicine, CA (United States)

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.

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Research Organization:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: USDOE National Nuclear Security Administration (NNSA)

Grant/Contract Number:: AC52-07NA27344

OSTI ID:: 1823222

Report Number(s):: LLNL-JRNL--774440; 965098

Journal Information:: Scientific Reports, Journal Name: Scientific Reports Journal Issue: 1 Vol. 11; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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