This research group want to develop an alternative strategy in respect of the already identified CFTR modulators drugs. They want to rescue F508del-CFTR improving the abnormal intracellular environment, considered the cause of the low mutated protein expression on the cell surface. To this aim, the combination of the TG2/PDI inhibitor cysteamine and the kinase inhibitor EGCG showed promising results. In this project researchers intend to refine these targets and search novel chemical entities by exploiting: a) in silico approaches like “Virtual Screening” and “Pharmacophoric Search”; b) in vitro/in cell assays of the best candidates against the specific targets (TG2, PDI, protein kinases); c) validation of the efficacy of the candidates in CF models (F508del-CFTR expressing cells, transgenic mice and primary nasal epithelial cells from F508del donors). The project may clarify the roles of several other protein targets in CF, beyond the F508del-CFTR; more it may pave the doors for a novel phase clinical study with a combination of molecules (or a single drug candidate) to treat F508del homozygotes CF patients.