Click-chemistry-derived oxime library reveals efficient reactivators of nerve agent-inhibited butyrylcholinesterase suitable for pseudo-catalytic bioscavenging DOI Creative Commons
Tena Čadež, Nikolina Maček Hrvat, Goran Šinko

и другие.

Archives of Toxicology, Год журнала: 2025, Номер unknown

Опубликована: Март 3, 2025

Abstract A library of 100 click-chemistry-derived oximes was evaluated as reactivators butyrylcholinesterase (BChE) inhibited by the nerve agents (NAs) sarin, cyclosarin, VX, and tabun. While reactivation efficiency highly dependent on structure both NA oxime, for each NA-BChE conjugate, we identified more effective than currently approved poisoning. Detailed kinetic analysis indicated that this enhancement results from improved molecular recognition—specifically, enhanced binding affinity phosphylated conjugates oximes—and increased maximal rates. Molecular modeling in a near-attack conformation within BChE revealed critical interactions productive reactivation. Among all tested oximes, 5B [1-hexyl-2-((hydroxyimino)methyl)pyridinium chloride] emerged particularly efficient reactivator phosphorylated with highest observed overall rate 34,120 M −1 min , which is 525-fold 44-fold higher reference 2-PAM HI-6, respectively. In general, three mono-pyridinium mono-oximes demonstrated recovery activity bis-pyridinium triazole-annulated click-chemistry bis-oximes, were previously potent acetylcholinesterase (AChE). Ex vivo assessment potency combined addition one another AChE achieved > 90% cyclosarin-inhibited cholinesterases whole blood (WB), demonstrating near-complete degradation 100-fold excess cyclosarin 6 min. These confirm oxime-assisted catalysis feasible bioscavenging underscore BChE’s potential target developing therapies against

Язык: Английский

Click-chemistry-derived oxime library reveals efficient reactivators of nerve agent-inhibited butyrylcholinesterase suitable for pseudo-catalytic bioscavenging DOI Creative Commons
Tena Čadež, Nikolina Maček Hrvat, Goran Šinko

и другие.

Archives of Toxicology, Год журнала: 2025, Номер unknown

Опубликована: Март 3, 2025

Abstract A library of 100 click-chemistry-derived oximes was evaluated as reactivators butyrylcholinesterase (BChE) inhibited by the nerve agents (NAs) sarin, cyclosarin, VX, and tabun. While reactivation efficiency highly dependent on structure both NA oxime, for each NA-BChE conjugate, we identified more effective than currently approved poisoning. Detailed kinetic analysis indicated that this enhancement results from improved molecular recognition—specifically, enhanced binding affinity phosphylated conjugates oximes—and increased maximal rates. Molecular modeling in a near-attack conformation within BChE revealed critical interactions productive reactivation. Among all tested oximes, 5B [1-hexyl-2-((hydroxyimino)methyl)pyridinium chloride] emerged particularly efficient reactivator phosphorylated with highest observed overall rate 34,120 M −1 min , which is 525-fold 44-fold higher reference 2-PAM HI-6, respectively. In general, three mono-pyridinium mono-oximes demonstrated recovery activity bis-pyridinium triazole-annulated click-chemistry bis-oximes, were previously potent acetylcholinesterase (AChE). Ex vivo assessment potency combined addition one another AChE achieved > 90% cyclosarin-inhibited cholinesterases whole blood (WB), demonstrating near-complete degradation 100-fold excess cyclosarin 6 min. These confirm oxime-assisted catalysis feasible bioscavenging underscore BChE’s potential target developing therapies against

Язык: Английский

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