β-淀粉样前体蛋白切割酶1抑制剂Atabecestat的生物活化导致谷胱甘肽s -转移酶Pi上蛋白质加合物的形成。

IF 3.7 3区医学 Q2 CHEMISTRY, MEDICINAL

Chemical Research in Toxicology Pub Date : 2025-05-19 Epub Date: 2025-05-06 DOI:10.1021/acs.chemrestox.5c00070

Megan Ford, Paul J Thomson, Adam Lister, Jan Snoeys, Laurent Leclercq, Filip Cuyckens, Dean J Naisbitt, Xiaoli Meng

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引用次数: 0

摘要

阿他司他暴露与肝损伤有关，肝损伤随后导致其停止发育。先前对阿他司他诱导的肝损伤患者的研究发现T细胞对阿他司他及其代谢物有反应，表明免疫介导的机制参与其中。由于不可逆的蛋白质修饰被怀疑驱动免疫原性，本研究旨在以HSA， GSTA1和GSTP作为模型蛋白来表征潜在的atabestat蛋白加合物。我们已经证明，在代谢系统存在的情况下，阿他司他只能在GSTP上形成半胱氨酸加合物，这突出了生物激活在加合物形成和结合相互作用选择性中的重要作用。

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Bioactivation of the β-Amyloid Precursor Protein-Cleaving Enzyme 1 Inhibitor Atabecestat Leads to Protein Adduct Formation on Glutathione S-Transferase Pi.

Exposure to atabecestat is associated with liver injury, which subsequently led to its withdrawal from development. Previous studies of patients with atabecestat induced liver injury identified T cells responsive to atabecestat and its metabolites, indicating that immune-mediated mechanisms are involved. As irreversible protein modification is suspected to drive immunogenicity, this study aimed to characterize potential atabecestat protein adducts using HSA, GSTA1, and GSTP as model proteins. We have shown that atabecestat only formed a cysteine adduct on GSTP in the presence of metabolic systems, highlighting the important role of bioactivation in adduct formation and selectivity for the binding interaction.

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来源期刊

Chemical Research in Toxicology 医学-毒理学

CiteScore

7.90

自引率

7.30%

发文量

215

审稿时长

3.5 months

期刊介绍： Chemical Research in Toxicology publishes Articles, Rapid Reports, Chemical Profiles, Reviews, Perspectives, Letters to the Editor, and ToxWatch on a wide range of topics in Toxicology that inform a chemical and molecular understanding and capacity to predict biological outcomes on the basis of structures and processes. The overarching goal of activities reported in the Journal are to provide knowledge and innovative approaches needed to promote intelligent solutions for human safety and ecosystem preservation. The journal emphasizes insight concerning mechanisms of toxicity over phenomenological observations. It upholds rigorous chemical, physical and mathematical standards for characterization and application of modern techniques.