CFTR Chloride Channel As A New Drug Target Of Anti-hypertensive Chinese Medicinal Herbs

Content: Cystic fibrosis transmembrane conductance regulator (CFTR) protein, a cAMP-activated Cl– channel, is expressed in airway, intestinal, pancreatic, and other secretory and absorptive epithelia, which is the only Cl- channel from ATP binding cassette(ABC) family. Recent study manifested that CFTR is also expressed in smooth muscle of blood vessel. CFTR function is closely related to many physiological and pathological disorders, such as Cystic fibrosis (CF)—the most prevalent hereditary lethal disease in Caucasians, idiopathic chronic pancreatiti (ICP), keratoconjunctivitis sicca, (KCS), habitual constipation, secretary diarrhea and polycystic kidney. Many attentions have been paid to the potential drug target role of CFTR.Many combinatorial small molecules have been identified to stimulat CFTR-mediate Cl- secretion. These small molecules may play key roles in study structure/function relationship of CFTR and elucidation pathology mechanism of CF. Due to the potential biological safety uncertatinty of these synthetic molecules, there is long way to go before clinical use of these combinatorial compounds. As the'chemical space'occupied by natural products is both more varied and more drug-like than that of combinatorial chemical collections, synthetic and biosynthetic methods are being developed to produce screening libraries of natural product-like compounds. So using the natural compounds to be lead compounds to develop new drugs become a hot spot of the new drug development. A renaissance of drug discovery inspired by natural products can be predicted. In this study, 104 CFTR activators were identiyfied from 386 natural compounds collections by using a cell-based fluorescence assay. Short-circuit current study and single submucasol gland fluid secretion measurement studies were used to systematically evaluation molecular mechanisms of several anti-hypertensive compounds (including coumarin, luteolin, and dictamnine). We demonstrated that the anti-hypertensive compounds could activate CFTR-mediate iodide influx in the cell-based fluorescence assay, and the activation was rapid, reversible and cAMP-dependent. coumarins ,luteolin, dictamnine activated wild-type and ?F508 mutant CFTR, curcumin can not activated G551D mutant CFTR. To be especially mentioned, osthole (a coumarin compound) stimulated fluid secretion at a speed of 3.33x10-10nl/s in the sigle submucosal gland fluid secretion study, and the activation could be reversed by CFTRinh-172. Our study also suggested a direct binding mechanism of CFTR activation by the anti-hypertension compounds, which suggested that CFTR may be one of the molecule targetes of these anti-hypertension medicines.Our studies also provide clues for elucidation molecular mechanism of anti-hypertensive TCM. The compound may be useful for probing CFTR channel gating mechanisms and as a lead compound to develop pharmacological therapy of CFTR-related disease such as cystic fibrosis, idiopathic chronic pancreatiti, keratoconjunctivitis sicca and habitual constipation.