Figuring out How a Cystic Fibrosis Drug Works♦

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Potentiator VX-770 (Ivacaftor) Opens the Defective Channel Gate of Mutant CFTR in a Phosphorylation-dependent but ATP-independent Manner
    Open AccessPublished:October 26, 2012DOI:
        Figure thumbnail gr1
        Schematic showing the potential mechanism of action of ivacaftor.
        ♦ See referenced article, J. Biol. Chem. 2012, 287, 36639–36649
        In January 2012, the United States Food and Drug Administration approved the small-molecule drug ivacaftor (VX-770), trademarked by Vertex Pharmaceuticals as Kalydeco, to treat a rare form of cystic fibrosis (CF) in patients aged 6 years and older. Ivacaftor is effective in treating the 4% of CF patients who have a specific mutation, G551D, in the CF transmembrane conductance regulator (CFTR) gene. CFTR is a chloride channel found in the epithelial lining of many organs, such as the airways, and is regulated by phosphorylation and ATP hydrolysis. However, details of ivacaftor's mode of action on the G551D mutation have been unclear. In this Paper of the Week, Christine E. Bear at the Hospital for Sick Children in Canada and colleagues demonstrated that the drug directly bound to the channel, rather than to associated proteins, such as kinases and phosphatases. Ivacaftor potentiated both mutant and wild-type CFTR channel activities, even in the absence of ATP. The findings suggest that the drug opens the channel by an ATP-independent, unconventional mechanism.