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

作者：Muangnil Paradorn; Satitsri Saravut; Tadpetch Kwanruthai; Saparpakorn Patchreenart; Chatsudthipong Varanuj; Hannongbua Supa; Rukachaisirikul Vatcharin; Muanprasat Chatchai^*

来源：Biochemical Pharmacology, 2018, 150: 291-302.

DOI：10.1016/j.bcp.2018.02.024

• Zearalenone
• Diarrhea
• CFTR
• Chloride channel
• Cholera

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 C1(-) 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 mu M. Functional and biochemical analyses and molecular docking studies indicate that zearalenone binds to the beta-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.

• 出版日期2018-4