The most common mutation in cystic fibrosis – F508del – is responsible for a defective folding of the chlorine channel CFTR which is not able to reach the plasma membrane. Patients affected by this mutation suffer from thick mucus in the respiratory tract and chronic inflammation with a short life expectancy. The current therapeutic approach points directly to the F508del-CFTR; unfortunately, only marginal benefits in lung function are observed. Researchers want to develop a novel strategy which aims at improving the intracellular environment causal of the low CFTR expression on the cell membrane. In particular, encouraging results have been obtained by the therapeutic combination of the TG2/PDI inhibitor cysteamine and the kinase inhibitor EGCG, as well as by the optimization of novel leads thanks to grants FFC#2/2016 and FFC#10/2017.
With this project, they will refine the new targets as a novel therapeutic strategy in CF by exploiting: a) in silico approaches to identify novel chemical entities by using consolidated techniques like Virtual Screening and Pharmacophoric search; b) in vitro/in cell assays of the best candidates against the specific targets (TG2/PDI, protein kinases, NRF2); c) validation of the efficacy of the novel drug candidates in CF models exploiting F508del-CFTR expressing cells, transgenic mice and primary nasal epithelial cells from F508del donors.