A fungal metabolite zearalenone as a CFTR inhibitor and potential therapy of secretory diarrheas

• Published in: Biochemical pharmacology Vol. 150; pp. 293 - 304
• Main Authors: Muangnil, Paradorn, Satitsri, Saravut, Tadpetch, Kwanruthai, Saparpakorn, Patchreenart, Chatsudthipong, Varanuj, Hannongbua, Supa, Rukachaisirikul, Vatcharin, Muanprasat, Chatchai
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01-04-2018
• Subjects: Animals; CFTR; Chloride channel; Cholera; Cystic Fibrosis Transmembrane Conductance Regulator - antagonists & inhibitors; Diarrhea; Diarrhea - drug therapy; Diarrhea - metabolism; Dose-Response Relationship, Drug; Fusarium; Male; Mice; Mice, Inbred ICR; Molecular Docking Simulation - methods; Protein Structure, Secondary; Zearalenone; Zearalenone - metabolism; Zearalenone - pharmacology; Zearalenone - therapeutic use; Diarrhea; Chloride channel; Zearalenone; Cholera; CFTR
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2018.02.024

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Overstimulation of CFTR-mediated Cl− secretion plays an important role in the pathogenesis of secretory diarrheas, which remain an important global health problem. 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.