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

Brian 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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number15567
JournalScientific reports
Volume11
Issue number1
DOIs
StatePublished - Dec 2021
Externally publishedYes

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Development of a CNS-permeable reactivator for nerve agent exposure: an iterative, multi-disciplinary approach'. Together they form a unique fingerprint.

Cite this