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Fluorine-thiol displacement probes for acetaminophen's hepatotoxicity

Acta Pharmaceutica Sinica B 2023年第1期13卷 204-212页

作者： Benjamin L.Prather Shuyue Ji Yue Zhao femil joseph shajan Mi Zhao Zakey Yusuf Buuh Robert Maloney Rui Zhang Carson Cohen Rongsheng E.Wang Department of Chemistry Temple UniversityPhiladelphiaPA 19122USA

Chemicals possessing reactive electrophiles can denature innate proteins leading to undesired toxicity,and the overdose-induced liver injury by drugs containing electrophiles has been one of the major causes of non-approval and withdraw by the US Food and Drug Administration(FDA).Elucidating the associated proteins could guide the future development of therapeutics to circumvent these drugs’toxicities,but was largely limited by the current probing tools due to the steric hindrance of chemical tags including the common“click chemistry”*** the widely used non-steroidal anti-inflammatory drug acetaminophen(APAP)as an example,we hereby designed and synthesized an APAP analogue using fluorine as a steric-free *** toxicity studies indicated our analogue has similar activity to the parent *** analogue was applied to the mouse hepatocellular proteome together with the corresponding desthiobiotinSH probe for subsequent fluorine-thiol displacement reactions(FTDRs).This set of probes has enabled the labeling and pull-down of hepatocellular target proteins of the APAP metabolite as validated by Western *** preliminary validation results supported the interaction of APAP with the thioredoxin protein,which is an important redox protein for normal liver *** results demonstrated that our probes confer minimal steric perturbation and mimic the compounds of interest,allowing for global profiling of interacting *** fluorine-thiol displacement probing system could emerge as a powerful tool to enable the investigation of drug-protein interactions in complex biological environments.

关键词： Acetaminophen(APAP) Liver Hepatotoxicity Bioorthogonal Click chemistry Fluorinedisplacement Fluorinethiol displacementreaction FTDR

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