Identification of Fungus‐derived Compounds as a Novel CFTR inhibitor: Mechanism and Potential Anti‐diarrheal Application

Abstract

Secretory diarrhea, which has been considered as a health burden worldwide, could be alleviated by inhibiting fluid secretion. CFTR is considered to be a drug target for development of anti‐secretory agent. However, there is no currently FDA‐approval drug targeting CFTR. This study aimed to identify CFTR inhibitors from a library of fungal bioactive metabolites found in Thailand. Electrophysiological analyses were used for identifying the inhibitory effect of 40 compounds. Three active compounds with the best one being DHLV, which effectively inhibited CFTR‐mediated Clˉ secretion with low micromolar potency (IC50 ~1.8 μM) in T84 cells without effect on Na+‐K+ ATPase activity. In addition, DHLV inhibited Ca2+‐activated Clˉ channels stimulated by ATP. In vivo experiments showed that administration of DHLV by intraperitoneal route (2 mg/kg) and intraluminal (22 µg/kg or 20 µM) injections reduced cholera toxin‐induced intestinal fluid secretion in mice by ∼46.7% and ∼42.8%, respectively without affecting intestinal fluid absorption. This study indicates that the novel CFTR inhibitor, DHLV, is of potential utility in the treatment of secretory diarrhea.