Friedreich 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 K147 in Calu-6 cells. A theoretical model of the frataxin-K147/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.
Discovery of a Novel Small Molecule Inhibitor Targeting the Frataxin/Ubiquitin Interaction via Structure-Based Virtual Screening and Bioassays / Lavecchia, A.; Di Giovanni, C.; Cerchia, C.; Russo, Annapina; Russo, Giulia; Novellino, E.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 56:7(2013), pp. 2861-2873. [10.1021/jm3017199]
Discovery of a Novel Small Molecule Inhibitor Targeting the Frataxin/Ubiquitin Interaction via Structure-Based Virtual Screening and Bioassays
Lavecchia A.;Di Giovanni C.;Cerchia C.;Russo Annapina;Russo Giulia;Novellino E.
2013
Abstract
Friedreich 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 K147 in Calu-6 cells. A theoretical model of the frataxin-K147/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.File | Dimensione | Formato | |
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Lavecchia et al, J Med Chem 2013.pdf
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