A novel image-based high-throughput screening assay discovers therapeutic candidates for adult polyglucosan body disease
| العنوان: | A novel image-based high-throughput screening assay discovers therapeutic candidates for adult polyglucosan body disease |
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| المؤلفون: | Peixiang Wang, Wyatt W. Yue, Or Kakhlon, Hanoch Senderowitz, Netaly Khazanov, Igor M. Ferreira, Leonardo J. Solmesky, Alexander Lossos, Miguel Weil, Berge A. Minassian |
| المصدر: | Biochemical Journal. 474:3403-3420 |
| بيانات النشر: | Portland Press Ltd., 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | Adult, Male, 0301 basic medicine, High-throughput screening, Cell, Phosphatase, Drug Evaluation, Preclinical, Biology, Biochemistry, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, medicine, Humans, Glycogen synthase, Molecular Biology, Glycogen, Cell Biology, Adult polyglucosan body disease, Fibroblasts, Glycogen Storage Disease, Glycogen Synthase, 030104 developmental biology, medicine.anatomical_structure, chemistry, biology.protein, Female, Nervous System Diseases, 030217 neurology & neurosurgery, Image based, Intracellular |
| الوصف: | Glycogen storage disorders (GSDs) are caused by excessive accumulation of glycogen. Some GSDs [adult polyglucosan (PG) body disease (APBD), and Tarui and Lafora diseases] are caused by intracellular accumulation of insoluble inclusions, called PG bodies (PBs), which are chiefly composed of malconstructed glycogen. We developed an APBD patient skin fibroblast cell-based assay for PB identification, where the bodies are identified as amylase-resistant periodic acid–Schiff's-stained structures, and quantified. We screened the DIVERSet CL 10 084 compound library using this assay in high-throughput format and discovered 11 dose-dependent and 8 non-dose-dependent PB-reducing hits. Approximately 70% of the hits appear to act through reducing glycogen synthase (GS) activity, which can elongate glycogen chains and presumably promote PB generation. Some of these GS inhibiting hits were also computationally predicted to be similar to drugs interacting with the GS activator protein phosphatase 1. Our work paves the way to discovering medications for the treatment of PB-involving GSD, which are extremely severe or fatal disorders. |
| تدمد: | 1470-8728 0264-6021 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1086baab83b2e045a92bb09570398a7bTest https://doi.org/10.1042/bcj20170469Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....1086baab83b2e045a92bb09570398a7b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14708728 02646021 |
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