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

Cell Chemical Biology
Elvira SondoNicoletta Pedemonte

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.

Citations

Jun 7, 2019·Expert Opinion on Therapeutic Targets·John W HanrahanDavid Y Thomas
Aug 21, 2019·Cold Spring Harbor Perspectives in Medicine·Katie A ThiesMichael C Ostrowski
Apr 5, 2020·International Journal of Molecular Sciences·Marco RusnatiPaola Fossa
Jul 1, 2020·International Journal of Molecular Sciences·Giulia ManciniMassimo Aureli
Oct 16, 2018·Frontiers in Pharmacology·Ryosuke Fukuda, Tsukasa Okiyoneda
Mar 5, 2020·Science Advances·Nicoletta PedemonteLuis J V Galietta
Mar 11, 2020·Frontiers in Pharmacology·Miquéias Lopes-Pacheco
Nov 5, 2019·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·Margarida D AmaralNicoletta Pedemonte
Jun 3, 2021·International Journal of Molecular Sciences·Valeria CapurroNicoletta Pedemonte

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