title: Potential Agents for Treating Cystic Fibrosis: Cyclic Tetrapeptides that Restore Trafficking and Activity of ΔF508-CFTR.
abstract: 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 (ΔF508), 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 cell surface activity of ΔF508-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 ΔF508-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 IC(50) values than reference agent vorinostat (2) in HDAC profiling, it was markedly more potent than 2 in rescuing ΔF508-CFTR. We suggest that specific HDACs can have a differential influence on correcting ΔF508-CFTR, which may reflect both deacetylase and protein scaffolding actions.
authors: Departments of Cell Biology, Chemical Physiology, and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors: Darren M
authors: DM
authors: Hutt
authors: Christian A
authors: CA
authors: Olsen
authors: Chris J
authors: CJ
authors: Vickers
authors: David
authors: D
authors: Herman
authors: Monica
authors: M
authors: Chalfant
authors: Ana
authors: A
authors: Montero
authors: Luke J
authors: LJ
authors: Leman
authors: Renner
authors: R
authors: Burkle
authors: Bruce E
authors: BE
authors: Maryanoff
authors: William E
authors: WE
authors: Balch
authors: M Reza
authors: MR
authors: Ghadiri