Treatment of Organophosphorus Exposure to Acetylcholinesterase by Small Molecule Therapeutics and by Catalytic Antibodies
2022
Online
Hochschulschrift
Organophosphorus (OP) agents are extremely toxic compounds that have been used as pesticides and chemical warfare agents. The mechanism of action by which OP compounds operate is the inhibition of the enzyme acetylcholinesterase (AChE), resulting in a cholinergic crisis and potentially death. Current treatments are limited and must be administered immediately upon exposure to an OP compound. After an OP compound inhibits AChE, a subsequent reaction, referred to as aging, occurs after a period of time that is dependent upon the chemical structure of the OP. The OP-aged forms of AChE are recalcitrant to current FDA-approved therapeutics and therefore it is of great importance to develop an effective treatment that is capable of restoring OP-aged AChE back to its native state. The Hadad group has shown that a class of compounds called quinone methide precursors (QMPs) are capable of converting OP-aged AChE back to its native state in a process referred to as resurrection. Herein is reported the synthesis of novel QMPs to be used as small molecule therapeutics for the treatment of OP-aged AChE. Additionally, the synthesis of pentacoordinate phosphorane haptens is reported, which are used to elicit the production of catalytic antibodies that selectively target and catalyze the hydrolysis of OP compounds before they have an opportunity to inhibit AChE; that is, this is a preemptive treatment akin to a vaccine. Finally, the synthesis of various OP surrogates is reported, which are used to screen QMPs for their resurrection efficacy in vitro.
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Treatment of Organophosphorus Exposure to Acetylcholinesterase by Small Molecule Therapeutics and by Catalytic Antibodies
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Autor/in / Beteiligte Person: | Ward, Nathan Andrew |
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Veröffentlichung: | 2022 |
Medientyp: | Hochschulschrift |
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