期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 56, 期 7, 页码 2861-2873出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm3017199
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资金
- Ministero dell'Istruzione, dell'Universita e della Ricerca Scientifica e Tecnologica, Rome, Italy [prot. 2010W7YRLZ_003]
Friedreich's ataxia (FRDA) is an autosomal recessive neuro- and cardiodegenerative disorder for which there are no proven effective treatments. FRDA is caused by decreased expression and/or function of the mitochondrial protein frataxin. Here, we report findings that frataxin is degraded via the ubiquitin proteasomal pathway and that it is ubiquitinated at residue K-147 in Calu-6 cells. A theoretical model of the frataxin-K-147/Ub complex, constructed by combining bioinformatics interface predictions with information-driven docking, revealed a hitherto unnoticed, potential ubiquitin-binding domain in frataxin. Through structure-based virtual screening and cell-based assays, we discovered a novel small molecule (compound (+)-11) able to prevent frataxin ubiquitination and degradation. (+)-11 was synthesized and tested for specific binding to frataxin by an UF-LC/MS based ligand-binding assay. Follow-up scaffold-based searches resulted in the identification of a lead series with micromolar activity in disrupting the frataxin/Ub interaction. This study also suggests that frataxin could be a potential target for FRDA drug development.
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