Screening for E3-Ubiquitin ligase inhibitors: challenges and opportunities

Screening for E3-Ubiquitin ligase inhibitors: challenges and opportunities. Vivien Landré, Barak Rotblat, Sonia Melino, Francesca Bernassola and Gerry Melino; Oncotarget, Published: September 03, 2014, Advance Publications

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Another interesting approach to inhibit ubiquitination of a specific substrate is to block the ubiquitination of the target rather than blocking the E3 ligase and therefore the ubiquitination of all its targets. This was demonstrated by a study that identified an inhibitor of the ubiquitination of frataxin, a mitochondrial protein whose downregulation is linked to Friedreich’s ataxia, a neuro-and cardiodegenerative disorder. Lavecchia et al.identified the ubiquitination site on frataxin and modelled the position of ubiquitin on the protein surface using in silico docking programs. Next, they used structure based virtual screening coupled with a cell-based assay of the 13 top hits, and identified a small molecule that disrupts the frataxin-ubiquitin interactions and thereby inhibits frataxin ubiquitination.