Pharmacological Inhibition of the Ubiquitin Ligase RNF5 Rescues F508del-CFTR in Cystic Fibrosis Airway Epithelia

Elvira Sondo, Federico Falchi, Emanuela Caci, Loretta Ferrera, Elisa Giacomini, Emanuela Pesce, Valeria Tomati, Sine Mandrup Bertozzi, Luca Goldoni, Andrea Armirotti, Roberto Ravazzolo, Andrea Cavalli, Nicoletta Pedemonte

Research output: Contribution to journalArticle

Abstract

In cystic fibrosis (CF), deletion of phenylalanine 508 (F508del) in the CFTR channel is associated with misfolding and premature degradation of the mutant protein. Among the known proteins associated with F508del-CFTR processing, the ubiquitin ligase RNF5/RMA1 is particularly interesting. We previously demonstrated that genetic suppression of RNF5 in vivo leads to an attenuation of intestinal pathological phenotypes in CF mice, validating the relevance of RNF5 as a drug target for CF. Here, we used a computational approach, based on ligand docking and virtual screening, to discover inh-02, a drug-like small molecule that inhibits RNF5. In in vitro experiments, treatment with inh-02 modulated ATG4B and paxillin, both known RNF5 targets. In immortalized and primary bronchial epithelial cells derived from CF patients homozygous for the F508del mutation, long-term incubation with inh-02 caused significant F508del-CFTR rescue. This work validates RNF5 as a drug target for CF, providing evidence to support its druggability.

Original languageEnglish
Pages (from-to)891-905.e8
JournalCell Chemical Biology
Volume25
Issue number7
DOIs
Publication statusPublished - Jul 19 2018

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Sondo, E., Falchi, F., Caci, E., Ferrera, L., Giacomini, E., Pesce, E., Tomati, V., Mandrup Bertozzi, S., Goldoni, L., Armirotti, A., Ravazzolo, R., Cavalli, A., & Pedemonte, N. (2018). Pharmacological Inhibition of the Ubiquitin Ligase RNF5 Rescues F508del-CFTR in Cystic Fibrosis Airway Epithelia. Cell Chemical Biology, 25(7), 891-905.e8. https://doi.org/10.1016/j.chembiol.2018.04.010