The Design and Synthesis of Small Molecule Therapeutics and Vaccine Prophylactics as Medical Solutions for Organophosphorus Exposure
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Date
2025-05
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The Ohio State University
Abstract
Organophosphorus (OP) compounds pose a serious health risk to humans through the inhibition of acetylcholinesterase (AChE). AChE is a vital enzyme responsible for hydrolyzing the neurotransmitter acetylcholine (ACh), which plays the primary role in muscle contraction and nerve signaling. OP compounds inhibit AChE through the phosphylation of the catalytic serine residue, preventing hydrolysis of ACh, leading to cholinergic crisis and death. Current therapeutics include oxime moieties that operate via a nucleophilic attack on the phosphylated serine residue of some OP-inhibited forms of AChE, a process which has been coined reactivation. However, oximes are limited by a lack of broad-scope reactivation, and they are ineffective at crossing the blood-brain barrier due to their permanent positive charge, thus limiting reactivation of AChE within the central nervous system (CNS). OP-inhibited AChE can also undergo a spontaneous O-dealkylation process, coined aging, in which current therapeutics do not offer any recovery.
In 2018, the Hadad lab reported a class of quinone methide precursors (QMPs) that were the first therapeutics to show evidence of recovery of the OP-aged form of the enzyme in a process termed resurrection. These QMPs have since been iterated and are able to recover both the inhibited and aged forms of AChE. Furthermore, due to being neutral, these QMP compounds have been shown to penetrate the BBB, increasing therapeutic efficacy compared to oximes. However, despite these strides toward better therapeutics, these QMPs still lack broad-scope reactivation and resurrection efficacy, and thus more research is being performed to optimize their activities. Herein, we report a novel library of 4-pyrrolylphenol and 6-pyrrolylpyridinol QMPs that show broad-scope reactivation of several OP-inhibited forms and resurrection of several OP-aged forms of AChE.
Following the discussion of QMPs, the design and synthesis of antigenic determinants as a method of prophylactic treatment to produce catalytic antibodies against OP compounds is discussed.