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In the gut, CFTR is crucial for maintaining fluid and acid\u2010base homeostasis, and its activity is tightly controlled by multiple neuro\u2010endocrine factors. However, microbial toxins can disrupt this intricate control mechanism and trigger protracted activation of CFTR. This results in the massive faecal water loss, metabolic acidosis and dehydration that characterize secretory diarrhoeas, a major cause of malnutrition and death of children under 5\u00a0years of age. Compounds that inhibit CFTR could improve emergency treatment of diarrhoeal disease. Drawing on recent structural and functional insight, we discuss how existing CFTR inhibitors function at the molecular and cellular level. We compare their mechanisms of action to those of inhibitors of related ABC transporters, revealing some unexpected features of drug action on CFTR. Although challenges remain, especially relating to the practical effectiveness of currently available CFTR inhibitors, we discuss how recent technological advances might help develop therapies to better address this important global health need.<\/jats:p>","DOI":"10.1002\/1873-3468.13971","type":"journal-article","created":{"date-parts":[[2020,10,28]],"date-time":"2020-10-28T21:06:38Z","timestamp":1603919198000},"page":"4085-4108","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Strategies for cystic fibrosis transmembrane conductance regulator inhibition: from molecular mechanisms to treatment for secretory diarrhoeas"],"prefix":"10.1002","volume":"594","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7596-7433","authenticated-orcid":false,"given":"Hugo R.","family":"de Jonge","sequence":"first","affiliation":[{"name":"Department of Gastroenterology &amp; Hepatology Erasmus University Medical Center Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria C.","family":"Ardelean","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Physiology and Pharmacology University College London UK"},{"name":"Department of Natural Sciences University College London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0814-188X","authenticated-orcid":false,"given":"Marcel J. 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