Discovery of a Novel Small Molecule Inhibitor Targeting the Frataxin/Ubiquitin Interaction via Structure-Based Virtual Screening and Bioassays

作者：Lavecchia Antonio^*; Di Giovanni Carmen; Cerchia Carmen; Russo Annapina; Russo Giulia; Novellino Ettore

来源：Journal of Medicinal Chemistry, 2013, 56(7): 2861-2873.

DOI：10.1021/jm3017199

Friedreich%26apos;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.

• 出版日期2013-4-11