The chemical optimization of cysteamine led to a novel compound (CT11), active in restoring CFTR-F508delfunction equally to cysteamine in cell models (CFBE41o-), but at a concentration 500 fold lower. These results were confirmed also in ex vivo experiments in nasal cells collected by nasal brushing from CF patients and in CFTR-F508del homozygous mice. Further, researchers carried out a selection of natural compounds and obtained the discovery of a three natural molecules (AC1, AC2, AC3) able to restore between 50-78% of CFTR-F508del function in cell models (CFBE41o-) and novel PDI inhibitors active in restoring CFTR-F508del function. Three compounds (SPH1, SPH2 and SEC1) with PDI inhibitory activity shew promising characteristics in restoring CFTR-F508del function in cell models. The project FFC#10/2017 will exploit essentially the same methodology previously described with the aim to develop a novel generation of optimized compounds against TG2, PDI and protein kinases.