Pharmacological interventions for the correction of ion transport defect in cystic fibrosis

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated and ATP-gated Cl^- channel expressed in the apical plasma membrane of epithelial cells in the airways, digestive and reproductive tracts. Cystic fibrosis (CF) caused by mutations in the CFTR gene is characterised by chronic airway obstructions and infections, pancreatic failure, male infertility and elevated levels of salt in sweat. A pharmacological therapy would help to restore the defective transepithelial Cl^- transport observed in CF cells. Therefore, searching for potent and specific small molecules or peptides able to stimulate transepithelial Cl^- transport through direct interaction with CFTR or via CFTR-independent mechanisms has become a crucial end point in the field. With the growing understanding of the pharmacology of CFTR activity and processing, a number of academic investigators and biopharmaceutical companies have developed high-throughput screening assays, and reported active seeking of CFTR activators or modulators of airway functions in order to treat CF. This article provides an updated overview of the new emerging molecules and discusses the corresponding patent literature.

• amiloride-sensitive Na+ channel (ENaC)
• cystic fibrosis therapy
• cystic fibrosis transmembrane conductance regulator (CFTR) Cl^- channel
• epithelial K+ channels
• epithelial secretion
• high-throughput screening (HTS)
• pharmacology
• polypeptides
• small molecules