DKP Development as Treatment for OP Nerve Agent Poisioning

Isabel Solowiej ’22

Students: Isabel Solowiej ’22 and Rebecca Hölzel ’22 (Kenyon College)
Research Mentors: Christopher Hadad, Ryan Yoder, and Joseph Fernandez (The Ohio State University Department of Chemistry and Biochemistry)

Chemical nerve agents are a lethal branch of weaponry that lack a widely effective and available treatment, resulting in thousands of exposures and deaths each year. The FDA approved treatment for nerve agent exposure is lacking, as the treatment cannot access all damage caused. This project explores a new approach to nerve agent treatment with a new molecule component, a diketopiperazine (DKP), allowing therapeutics to easily access all nerve agent damage in the body.

Exposure to organophosphorus (OP) nerve agents and pesticides presents a threat to health, safety, and national security. OP nerve agents inhibit acetylcholinesterase (AChE), an enzyme found in the nervous system, neuromuscular junctions, and red blood cells designed to hydrolyze the neurotransmitter, acetylcholine (ACh). OP compounds phosphylate the catalytically active serine residue of AChE, inhibiting the enzyme from performing hydrolysis. Certain nucleophilic oximes have been identified as a treatment in the event of OP nerve agent exposure, reactivating the inhibited serine residue. These therapeutics are limited in effectiveness because of challenges in crossing the blood brain barrier (BBB), limiting access to the inhibited AChE in the brain.

In response to this problem, we proposed the use of diketopiperazines (DKPs) as transport agents to create a shuttle that allows the oxime reactivator to cross the BBB. The initial shuttle design included a peptoid BBB shuttle component, linker component, and therapeutic component. Combinations of side chains, DKP linkers, and oxime reactivators were examined through Epik protonation prediction, Gaussian quantum mechanical optimization, AutoDockFR docking, and SwissADME drug efficacy prediction for VX and sarin nerve agents. Compounds with no net charge or masked charges, likelihood to exist at physiological pH, and shortest oxime-phosphorous reactive distances were identified as lead compounds. Straight chain linker components and arginine or tBu protected glutamate side chains were generally preferred for reactivation potential. No difference was apparent between therapeutic oxime reactivators. A set of four DKP compounds with overall greatest potential to be effective treatments for VX and sarin inhibited AChE were selected to move forward for synthesis, in vitro testing, and in vivo testing.