What is the link between the inherited disorder cystic fibrosis and secretory diarrhoea, the biggest killer of children under 5 years of age in developing countries? The answer is the cystic fibrosis transmembrane conductance regulator (CFTR) — a cyclic-AMP-activated chloride channel that is responsible for fluid secretion in the intestines and airways. Mutations in the CFTR gene that inactivate the function of the protein lead to cystic fibrosis, and the cholera toxin that causes secretory diarrhoea induces intestinal fluid secretion by affecting CFTR-mediated Cl− transport. But, so far, the development of treatments that target CFTR has been hampered by the lack of appropriate small-molecule inhibitors to help researchers investigate the relevant pathophysiological mechanisms and potential therapies.

Now, in the Journal of Clinical Investigation, Verkman and colleagues report the identification of a class of high-affinity CFTR inhibitors from a screen of 50,000 compounds. They found that six compounds, all thiazolidinones, were potent inhibitors of CFTR-mediated Cl− transport, and worked in the submicromolar range. The most potent of these inhibitors blocked Cl− tranport in CFTR, but did not inhibit other Cl− channels or transporters. This inhibitor was non-toxic in cell-culture and mouse models, and a single dose in mice reduced cholera-toxin-induced fluid secretion by 90% for over 6 hours.

CFTR inhibitors could help advance the development of treatments for secretory diarrhoea and cystic fibrosis in different ways. For secretory diarrhoea, thiazolidinones could provide an alternative line of attack to oral rehydration therapy, which revolutionized the treatment of secretory diarrhoea by single-handedly reducing the mortality of children by more than half. For cystic fibrosis, identifying therapies has been difficult owing to a lack of adequate human-tissue and animal models with impaired CFTR function. But thiazolidinones could at last provide researchers with the much-needed tools to investigate the underlying pathophysiological pathways of this fatal genetic disease.