Identification of cftr activators and inhibitors: chance or design?

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated Cl(-) channel expressed in various epithelial cells, and is a pharmacological target for activators and inhibitors. Activators are useful for the pharmacotherapy of cystic fibrosis, specifically for those mutations that affect CFTR protein by reducing its ability to stay in the open state. Conversely, inhibitors are potentially useful to treat secretory diarrhoea caused by enterotoxins, as the CFTR is the main route for Cl(-) flux in the intestine. Recently, a variety of potent modulators of the CFTR Cl(-) channel activity have been identified by high-throughput screening of a large collections of small molecules. The identification of CFTR activators and inhibitors with novel chemical scaffolds might help with the rational design of compounds with improved pharmacological properties.