Researchers discover the first nerve-agent antidote that crosses the blood–brain barrier

A team led by LLNL scientists has discovered the first antidote against nerve-agent poisoning that crosses the blood–brain barrier (BBB). Their research, published in Scientific Reports, comes on the heels of a recent resurgence of nerve agents in transnational conflicts.

Organophosphorus-based nerve agents (OPNAs)—including sarin, soman, and VX—cross the BBB and are arguably the most dangerous chemicals ever manufactured due to their lethality and ease of production. These highly poisonous substances disrupt the peripheral and central nervous systems (PNS, CNS) by deactivating the enzyme acetylcholinesterase (AChE), which leads to an excess of acetylcholine, a neurotransmitter responsible for muscle activation. The dangerous buildup results in involuntary muscle contractions, seizures, and eventually death. Current antidotes use small molecule-based chemical compounds to restore AChE but work primarily in the PNS. For example, the FDA-approved 2-pralidoxime (2-PAM) reactivates AChE but has a positively charged nitrogen center that prevents it from permeating the BBB to reach the CNS.

In search of a fast-acting therapeutic effective in the PNS as well as the CNS, the team implemented a multidisciplinary approach. With a combination of organic synthesis, computational modeling, and a battery of detailed in vitro and in vivo assays, they discovered a novel CNS-permeable compound. Named LLNL-02, it protects the peripheral and central nervous systems by virtue of its ability to cross the BBB.

The Defense Threat Reduction Agency has already approved subsequent animal studies to assess acute and chronic toxicity, which will be carried out at the Lab. Although their efforts are ongoing, the group’s initial finding represents a significant breakthrough in nerve-agent countermeasures.

[B.J. Bennion, M.A. Malfatti, N.A. Be, H.A. Enright, S. Hok, C.L. Cadieux, T.S. Carpenter, V. Lao, E.A. Kuhn, M.W. McNerney, F.C. Lightstone, T.H. Nguyen, and C.A. Valdez, Development of a CNS-permeable reactivator for nerve agent exposure: an iterative, multi-disciplinary approach, Scientific Reports 11, 15567 (2021).]