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

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 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.