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Analyses of interactions between organophosphorus compounds and esterases and other targets for therapy in poisoning

Project type
Znanstveno-istraživački projekti
Research Projects
Croatian Science Foundation
Start date
Dec 16th 2023
End date
Dec 15th 2027
Total cost
198818 EUR

Exposure to organophosphates (OP) from both pesticides and nerve agents leads to the covalent inhibition of the pivotal enzyme acetylcholinesterase (AChE) that leads to accumulation of neurotransmitter acetylcholine, which induces cholinergic crisis, that is, overstimulation of muscarinic and nicotinic membrane receptors in the central and peripheral nervous system. In severe cases, subsequent desensitisation of the receptors results in hypoxia, vasodepression, and respiratory arrest, followed by death. Prompt action is therefore critical to improve the chances of victim's survival and recovery. Standard therapy of OP poisoning generally involves administration of anticholinergic atropine and an oxime reactivator of phosphylated AChE. The related enzyme butyrylcholinesterase (BChE) in human tissues binds OP compounds and as such acts as stochiometric bioscavenger of OP. Due to structural requirements, their binding affinity and reactivation rate have not been well-balanced. Therefore, this project utilizes known and new compounds to gain a better understanding of the mechanistic basis of cholinesterase family interactions and their limitations to find new effective leads for further in vivo study. The biochemical mechanism of enzyme interactions will be comprehensively studied on a molecular level with in silico, in vitro, and ex vivo methods. Kinetic constants of the studied interactions will be determined based on known kinetic models, while in need of unusual regression analysis new kinetic models will be developed. We will combine several approaches, including: a study of the finely tuned interplay between these two sister enzymes, computational and in vitro experimental studies of cholinesterase interactions with a wide range of ligands defining favourable characteristic for potential new antidotes in vivo. This will also enable us to explore other possible OP treatments such as highly-effective bioscavengers based on efficient reactivation of OP-inhibited BChE. These comprehensive analyses will explain structural requirements for compounds interacting with BChE and gain a platform for synthesis of reactivators of phosphylated BChE and potentially active drugs in disorders that involve interactions with BChE.

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