title: Discovery of a novel small molecule inhibitor targeting the frataxin/ubiquitin interaction via structure-based virtual screening and bioassays.
abstract: 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.
authors.affiliation: Dipartimento di Chimica Farmaceutica e Tossicologica, Drug Discovery Laboratory, Università di Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy. lavecchi@unina.it
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.forename: Carmen
authors.initials: C
authors.lastname: Di Giovanni
authors.forename: Carmen
authors.initials: C
authors.lastname: Cerchia
authors.forename: Annapina
authors.initials: A
authors.lastname: Russo
authors.forename: Giulia
authors.initials: G
authors.lastname: Russo
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
mesh_terms: D001681:Biological Assay; D015153:Blotting, Western; D002853:Chromatography, Liquid; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D033862:Iron-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013058:Mass Spectrometry; D008958:Models, Molecular; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D025801:Ubiquitin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000096923:Frataxin
chemical_list: D033862:Iron-Binding Proteins; D054852:Small Molecule Libraries; D025801:Ubiquitin; D000096923:Frataxin