Strategies for cystic fibrosis transmembrane conductance regulator inhibition: from molecular mechanisms to treatment for secretory diarrhoeas

Abstract

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.

Network Pharmacology-Based Validation of the Efficacy of Huiyangjiuji Decoction in the Treatment of Experimental Colitis

“…GO and KEGG analysis showed that AMK, PSW and SCF target genes were not only enriched in neurological pathways, including neuroactive ligand-receptor interaction and neurotransmitter receptor activities, but also contributed to digestive functions, such as protein digestion and absorption, as well as salivary secretion. Many of these effects were seemingly rather indirectly combating secretory diarrhea frequently occurring during IBD (Schiller, 1999), than directly interacting with the progression of IBD (Jonge et al, 2020). Additionally, given the high fiber in the components of HYJJ decoction and the improved gut health following ingestion of plant-based constituents (Carvalhana et al, 2012;Alferink et al, 2020), the intrinsic nature of these herb compounds was also beneficial for the gut recovery.…”

Age-associated changes in lineage composition of the enteric nervous system regulate gut health and disease

“…While the co-expression of aforementioned pan-neuronal markers establishes the neuronal nature of MENs, the expression of set of key genes in MENs suggests putative specialized functional roles of these subpopulations when they co-exist with NENs in adults. These include the expression of genes associated with putative sensory (Calcb) 115 , neuromodulatory (Ntf3) 116 , secretory (Cftr) 117 , immunomodulatory (Il18) 2 , hormone regulating (Ghrh) 118 , extracellular matrix (ECM)-modulating (Dcn), and motility-regulating roles (Slc17a9 or VNUT) 119 . These MEN-enriched or MEN-specific expression profiles suggest that MENs perform various roles in the regulation of diverse gastrointestinal functions.…”

A Potential Treatment of Congenital Sodium Diarrhea in Patients With Activating GUCY2C Mutations

“…1 Division of Pediatrics, Department of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht (UMCU), Utrecht University (UU), Utrecht, the Netherlands; 2 Regenerative Medicine Center, UMCU, UU, Utrecht, the Netherlands; 3 Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands; 4 Newborn Research Z ürich, Department of Neonatology, University Hospital Zurich and University of Zurich, Zurich, Switzerland; 5 Institute of Physiology, University of Zurich, Zurich, Switzerland; 6 Kinder-und Jugendmedizin, Helios Klinikum, Krefeld, Germany;…”

“…GCC ligand binding increases the intracellular cyclic guanosine monophosphate (cGMP) level, which triggers protein kinase–mediated activation of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and inhibition of the sodium-proton exchanger NHE3. This dual action promotes the retention of salt and water in the gut lumen ( 2 , 5 ), and abnormally high GCC activity leads to diarrhea.…”