Rescuing ΔF508 CFTR with trimethylangelicin, a dual-acting corrector and potentiator.

Since the discovery of the cystic fibrosis (CF) gene that encodes the CF transmembrane conductance regulator (CFTR) in 1989, there has been considerable progress in understanding the molecular defects associated with different mutations in the CFTR protein. Small molecule "potentiators" have led the way as a drug therapeutic approach for correcting channel gating mutations such as the G551D mutation. Therapies for correcting the most common folding mutation in CFTR, ΔF508, however, have proven to be much more challenging. The protein-folding problem appears to be associated with both nucleotide binding domain (NBD) instability and domain interface interactions that are caused by the loss of the phenylalanine residue in NBD 1. Given the inherent complexity in the sequential folding pathway for this very large multidomain protein, it has been suggested that correcting the proper folding, anion channel function, and cell surface stability of the ΔF508 CFTR protein will require a multidrug approach to fix each of these compounding problems. Here we discuss a recent publication (Favia M, Mancini MT, Bezzerri V, Guerra L, Laselva O, Abbattiscianni AC, Debellis L, Reshkin SJ, Gambari R, Cabrini G, Casavola V. Am J Physiol Lung Cell Mol Physiol 307: L48-L61, 2014), however, that offers hope that single drug therapies are still possible.