Strategies for cystic fibrosis transmembrane conductance regulator inhibition: from molecular mechanisms to treatment for secretory diarrhoeas
Cystic fibrosis transmembrane conductance regulator (CFTR) is an unusual ABC transporter. It acts as an anion-selective channel that drives osmotic fluid transport across many epithelia. In the gut, CFTR is crucial for maintaining fluid and acid-base homeostasis, and its activity is tightly controlled by multiple neuro-endocrine 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 years 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.
|CFTR pharmacology, cholera, cyclic AMP, cyclic GMP, enterocyte, G907 compound, glibenclamide, ion-channel gating, secretory diarrhea, zosuquidar|
|F E B S Letters|
|Organisation||Department of Gastroenterology & Hepatology|
de Jonge, H.R, Ardelean, M.C. (Maria C.), Bijvelds, M.J.C, & Vergani, P. (Paola). (2020). Strategies for cystic fibrosis transmembrane conductance regulator inhibition: from molecular mechanisms to treatment for secretory diarrhoeas. F E B S Letters. doi:10.1002/1873-3468.13971