Oridonin: a small molecule inhibitor of cystic fibrosis transmembrane conductance regulator (CFTR) isolated from traditional Chinese medicine.

The cystic fibrosis transmembrane conductance regulator (CFTR) is an epithelial chloride channel regulating the transepithelial transport of electrolyte and water. In the recent years, CFTR chloride channel becomes the new molecular target of treating secretory diarrhea. The objective of this study is to find out a novel CFTR inhibitor from traditional Chinese medicine (TCM) and study on its pharmacological activity. About 34,000 factions of TCM extracts were screened by high throughput screening (HTS) in this research. We found that Rabdosia rubescens show a potent inhibition on CFTR. Under the bio-active analysis guidance, an ent-kaurane diterpenoid - oridonin (PubChem CID: 34378) was isolated from R. rubescens. A series of intensive studies showed that oridonin remarkably reduced iodide influx in wt-CFTR and ΔF508-CFTR FRT epithelial cells in a dose-dependent and irreversible way. Oridonin sharply blocked FSK-stimulated short-circuit current in both rats and mice intestine in vitro. In mouse closed-loop model, oridonin reduced cholera toxin-induced fluid secretion significantly over 6hours in vivo. Thus we concluded that oridonin is a new inhibitor of CFTR Cl(-) channel. It will be a good leading compound for developing the new drug of cholera toxin-induced secretory diarrhea.