2. Academic Validation
  3. Pharmacological Inhibition of the Ubiquitin Ligase RNF5 Rescues F508del-CFTR in Cystic Fibrosis Airway Epithelia

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

  • Cell Chem Biol. 2018 Jul 19;25(7):891-905.e8. doi: 10.1016/j.chembiol.2018.04.010.
Elvira Sondo 1,  Federico Falchi 2,  Emanuela Caci 1,  Loretta Ferrera 1,  Elisa Giacomini 3,  Emanuela Pesce 1,  Valeria Tomati 1,  Sine Mandrup Bertozzi 4,  Luca Goldoni 4,  Andrea Armirotti 4,  Roberto Ravazzolo 5,  Andrea Cavalli 6,  Nicoletta Pedemonte 7
Affiliations

Affiliations

  • 1 U.O.C. Genetica Medica, Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, Genova 16147, Italy.
  • 2 Dipartimento di Farmacia e Biotecnologie, University of Bologna Alma Mater Studiorum, Bologna 40126, Italy; D3 Compunet, Fondazione Istituto Italiano di Tecnologia, Genova 16163, Italy.
  • 3 D3 Compunet, Fondazione Istituto Italiano di Tecnologia, Genova 16163, Italy.
  • 4 Analytical Chemistry Facility, Fondazione Istituto Italiano di Tecnologia, Genova 16163, Italy.
  • 5 U.O.C. Genetica Medica, Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, Genova 16147, Italy; DINOGMI Department, University of Genova, Genova 16132, Italy.
  • 6 Dipartimento di Farmacia e Biotecnologie, University of Bologna Alma Mater Studiorum, Bologna 40126, Italy; D3 Compunet, Fondazione Istituto Italiano di Tecnologia, Genova 16163, Italy. Electronic address: andrea.cavalli@unibo.it.
  • 7 U.O.C. Genetica Medica, Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, Genova 16147, Italy. Electronic address: nicoletta.pedemonte@unige.it.
PMID: 29754957 DOI: 10.1016/j.chembiol.2018.04.010
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.

Keywords

CFTR; chloride channel; cystic fibrosis; proteostasis; therapy; ubiquitylation; virtual screening.

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