A fungal metabolite zearalenone as a CFTR inhibitor and potential therapy of secretory diarrheas.
This study aimed to identify inhibitors of CFTR-mediated Cl- secretion from a library of fungus-derived compounds and to evaluate their pharmacological properties and anti-diarrheal utility. We identified zearalenone, 7'-dehydrozearalenone and 8'-hydroxyzearalenone isolated from the seagrass-derived fungus Fusarium sp. PSU-ES123 as inhibitors of CFTR-mediated Cl- secretion in human intestinal epithelial (T84) cells. Being the most potent fungal metabolite capable of inhibiting CFTR-mediated Cl- secretion, zearalenone reversibly inhibited CFTR Cl- channel activity in T84 cells with an IC50 of ∼ 0.5 μM. Functional and biochemical analyses and molecular docking studies indicate that zearalenone binds to the β-estradiol binding sites in the ATP-binding pockets on NBD1 and NBD2 of CFTR. Mechanisms of CFTR inhibition by zearalenone do not involve activation of phosphodiesterases, protein phosphatases, multidrug-resistance protein 4 and AMP-activated protein kinases. Importantly, zearalenone significantly inhibited cholera toxin (CT)-induced Cl- secretion in T84 cells and blocked CT-induced intestinal fluid secretion in mice. Collectively, our study indicates that zearalenone represents the first class of fungus-derived CFTR inhibitors. Further development of this class of compounds may provide an effective treatment of secretory diarrheas.
PMID: 29475061 [PubMed - as supplied by publisher]
Source: Biochemical Pharmacology - Category: Drugs & Pharmacology Authors: Muangnil P, Satitsri S, Tadpetch K, Saparpakorn P, Chatsudthipong V, Hannongbua S, Rukachaisirikul V, Muanprasat C Tags: Biochem Pharmacol Source Type: research
More News: Cholera | Databases & Libraries | Drugs & Pharmacology | Estradiol | Multidrug Resistance | Study