Potential Agents for Treating Cystic Fibrosis: Cyclic Tetrapeptides That Restore Trafficking and Activity of ΔF508-CFTR

Cystic fibrosis (CF) is a loss-of-function disease caused by mutations in the CF transmembrane conductance regulator (CFTR) protein, a chloride ion channel that localizes to the apical plasma membrane of epithelial cells. The most common form of the disease results from the deletion of phenylalanine-508 (Delta F508), leading to the accumulation of CFTR in the endoplasmic reticulum with a concomitant loss of chloride flux. We discovered that cyclic tetrapeptides, such as 11, 14, and 15, are able to correct the trafficking defect and restore the cell surface activity of Delta F508-CFTR. Although this class of cyclic tetrapeptides is known to contain inhibitors of certain histone deacetylase (HDAC) isoforms, their HDAC inhibitory potencies did not directly correlate with their ability to rescue Delta F508-CFTR. In full HDAC profiling, 15 strongly inhibited HDACs 1, 2, 3, 10, and 11 but not HDACs 4-9. Although 15 had less potent IC50 values than reference agent vorinostat (2) in HDAC profiling, it was markedly more potent than 2 in rescuing Delta F508-CFTR We suggest that specific HDACs can have a differential influence on correcting Delta F508-CFTR, which may reflect both deacetylase and protein scaffolding actions.