1. Academic Validation
  2. Discovery of a novel small molecule inhibitor targeting the frataxin/ubiquitin interaction via structure-based virtual screening and bioassays

Discovery of a novel small molecule inhibitor targeting the frataxin/ubiquitin interaction via structure-based virtual screening and bioassays

  • J Med Chem. 2013 Apr 11;56(7):2861-73. doi: 10.1021/jm3017199.
Antonio Lavecchia 1 Carmen Di Giovanni Carmen Cerchia Annapina Russo Giulia Russo Ettore Novellino
Affiliations

Affiliation

  • 1 Dipartimento di Chimica Farmaceutica e Tossicologica, Drug Discovery Laboratory, Università di Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy. lavecchi@unina.it
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.

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