A fungal metabolite zearalenone as a CFTR inhibitor and potential therapy of secretory diarrheas
© 2018 Elsevier Inc. 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 compound...
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th-mahidol.452012019-08-28T13:52:26Z A fungal metabolite zearalenone as a CFTR inhibitor and potential therapy of secretory diarrheas Paradorn Muangnil Saravut Satitsri Kwanruthai Tadpetch Patchreenart Saparpakorn Varanuj Chatsudthipong Supa Hannongbua Vatcharin Rukachaisirikul Chatchai Muanprasat Kasetsart University Mahidol University Prince of Songkla University Biochemistry, Genetics and Molecular Biology Pharmacology, Toxicology and Pharmaceutics © 2018 Elsevier Inc. 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 IC 50 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. 2019-08-23T10:35:09Z 2019-08-23T10:35:09Z 2018-04-01 Article Biochemical Pharmacology. Vol.150, (2018), 293-304 10.1016/j.bcp.2018.02.024 18732968 00062952 2-s2.0-85042716486 https://repository.li.mahidol.ac.th/handle/123456789/45201 Mahidol University SCOPUS https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85042716486&origin=inward |
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Biochemistry, Genetics and Molecular Biology Pharmacology, Toxicology and Pharmaceutics Paradorn Muangnil Saravut Satitsri Kwanruthai Tadpetch Patchreenart Saparpakorn Varanuj Chatsudthipong Supa Hannongbua Vatcharin Rukachaisirikul Chatchai Muanprasat A fungal metabolite zearalenone as a CFTR inhibitor and potential therapy of secretory diarrheas |
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© 2018 Elsevier Inc. 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 IC 50 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. |
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Kasetsart University |
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Kasetsart University Paradorn Muangnil Saravut Satitsri Kwanruthai Tadpetch Patchreenart Saparpakorn Varanuj Chatsudthipong Supa Hannongbua Vatcharin Rukachaisirikul Chatchai Muanprasat |
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Article |
author |
Paradorn Muangnil Saravut Satitsri Kwanruthai Tadpetch Patchreenart Saparpakorn Varanuj Chatsudthipong Supa Hannongbua Vatcharin Rukachaisirikul Chatchai Muanprasat |
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Paradorn Muangnil |
title |
A fungal metabolite zearalenone as a CFTR inhibitor and potential therapy of secretory diarrheas |
title_short |
A fungal metabolite zearalenone as a CFTR inhibitor and potential therapy of secretory diarrheas |
title_full |
A fungal metabolite zearalenone as a CFTR inhibitor and potential therapy of secretory diarrheas |
title_fullStr |
A fungal metabolite zearalenone as a CFTR inhibitor and potential therapy of secretory diarrheas |
title_full_unstemmed |
A fungal metabolite zearalenone as a CFTR inhibitor and potential therapy of secretory diarrheas |
title_sort |
fungal metabolite zearalenone as a cftr inhibitor and potential therapy of secretory diarrheas |
publishDate |
2019 |
url |
https://repository.li.mahidol.ac.th/handle/123456789/45201 |
_version_ |
1763496100944150528 |