The most frequent mutation in CF patients is the deletion of phenylalanine 508 (F508del), causing the mistrafficking of CFTR protein. The trafficking defect can be rescued by molecules called correctors. However, the efficacy of known compounds is rather weak. By studying proteins that interact with CFTR, the proponents of this study identified a protein named RNF5 whose inhibition can lead to mutant CFTR rescue, both in vitro and in vivo using animal models. The aims of the project are to discover small drug-like molecules able to inhibit RNF5 activity and to analyze the molecular mechanisms involved in CFTR rescue following RNF5 suppression. By means of a computational approach, a model of RNF5 protein will be generated and used to screen large libraries of compounds (>4M), to identify novel treatments with improved efficacy and selectivity, aimed to correct the basic defect associated to F508del- CFTR (45-50% of CF patients in Italy).