The Biophysics Institute has recently been granted funding by the Italian cystic fibrosis research Foundation to carry out a research project focusing on ‘Dissecting the rescue mechanisms mediated by CFTR correctors’. The project leader is Dr. Debora Baroni.
Cystic fibrosis is a lethal genetic disease caused by loss-of-function mutations in the CF transmembrane conductance regulator (CFTR) protein. Deletion of phenylalanine at position 508 (F508del) of the CFTR polypeptide is the mutation with the highest incidence among patients affected by Cystic fibrosis. It determines the synthesis of a protein with defects of folding, maturation and trafficking.
Several high-throughput screening campaigns have allowed the identification of compounds, called correctors, able to partially restore the correct folding of the mutant protein and allow a partial translocation to the plasma membrane. However, these substances have shown not only reduced efficacy but also serious limitations of use. Understanding the mechanism of action as well as identifying the corrector binding site on the CFTR protein becomes essential for the design of targeted drugs.
The project aims to identify the domains and subdomains of the CFTR protein involved in the rescue mechanism exerted by correctors in order to provide new and more detailed information for the drug discovery process.