As part of the search for new molecules capable of correcting the CFTR defect, the researchers focused on specific cellular targets, rather than the mutated channel, exploiting a network of computational and experimental approaches up to preclinical models. In particular, using different cell models, which included CFBE41o- cells and primary cells from patients, characterized by the presence of the F508del mutation, the researchers identified TG2, Nrf2 and specific protein kinases as promising targets in CF therapy. Consequently, they selected different families of compounds, found to be effective in restoring the levels and functionality of the CFTR channel. Furthermore, the researchers demonstrated that, although apparently unrelated, the newly identified targets co-participate in the same cellular events. Consequently, it was possible to demonstrate the effectiveness of the combination of the selected molecules in restoring the altered proteostasis in CF models and as a result in recovering a functional channel in the plasma membrane. Finally, such an approach, not being directed against the CFTR channel, has the potential to be mutation independent and, consequently, to be translated towards orphan mutations by effective therapy. In fact, some selected molecules, in addition to being active in models characterized by the presence of the more common F508del mutation, were also promising against the N1303K mutation.

Pubblications

• Sofia Zanin, Simone Molinari, Giorgio Cozza et al. Intracellular protein kinase CK2 inhibition by ferulic acid-based trimodal nanodevice, Int J Biol Macromol. 2020 Dec 15;165(Pt A):701-712
• Luca Fasolato, Massimiliano Magro, Giorgio Cozza et al. An Iron Shield to Protect Epigallocatehin-3-Gallate from Degradation: Multifunctional Self-Assembled Iron Oxide Nanocarrier Enhances Protein Kinase CK2 Intracellular Targeting and Inhibition, Pharmaceutics 2021 Aug 16;13(8):1266