Identification of a new molecule with readthrough activity to rescue CFTR protein function

In Cystic fibrosis (CF) disease nonsense mutations in the CFTR gene cause absence of the CFTR protein expression and a more severe form of the disease. About 10% of patient affected by CF show a nonsense mutation. A potential treatment of this alteration is to promote translational readthrough of premature termination codons (PTCs) by translational readthrough inducing drugs such as Ataluren. In this context we aimed to compare the 1,2,4-oxadiazole core of Ataluren with a slightly different scaffold, the 1,3,4oxadiazole core. By a validated protocol consisting of computational screening, synthesis and biological tests we identified, a new small molecule with 1,3,4-oxadiazole core (2a/NV2445) showing high readthrough activity. Moreover, we evaluated quantitatively the CFTR functionality after 2a/NV2445 treatment in CF model systems and in cells expressing a nonsense-CFTR-mRNA. Finally, we studied the supramolecular interactions among readthrough inducing drugs and CFTR mRNA to assess the biological target/mechanism and further we used the QikProp program to compare the ADME properties of 2a/NV2445 and Ataluren.