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The F508del-CFTR trafficking correctors elexacaftor and tezacaftor are CFTR-independent Ca-mobilizing agonists normalizing abnormal Ca levels in human airway epithelial cells.
Respir Res
December 2024
PRéTi, Université de Poitiers, Poitiers, France.
Background: Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) channel. For people with CF (pwCF) affected by the most common pathogenic variant F508del, a tritherapy, named Trikafta/Kaftrio (ETI: elexacaftor (VX-445) /tezacaftor (VX-661) / ivacaftor (VX-770)) was successfully developed. However, in CF airway epithelial cells the calcium homeostasis is also disturbed; it is observed an increased calcium mobilization in CF cells compared to non-CF cells.
View Article and Find Full Text PDFUnlabelled: Trikafta is well-known for correcting the thermal and gating defects caused by the most common cystic fibrosis mutation F508del in the human cystic fibrosis transmembrane conductance regulator even at physiological temperature. However, the exact pathway is still unclear. Here, the noncovalent interactions among two transmembrane domains (TMD 1 and TMD2), the regulatory (R) domain and two nucleotide binding domains (NBD1 and NBD2), along with the thermoring structures of NBD1, were analyzed around the active gating center.
View Article and Find Full Text PDFNext generation triplex-forming PNAs for site-specific genome editing of the F508del CFTR mutation.
J Cyst Fibros
August 2024
Department of Pediatrics, Yale School of Medicine, New Haven, CT 06520, USA; Department of Cellular and Molecular Physiology Yale School of Medicine, New Haven, CT 06520, USA. Electronic address:
Background: Cystic Fibrosis (CF) is an autosomal recessive genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein for which there is no cure. One approach to cure CF is to correct the underlying mutations in the CFTR gene. We have used triplex-forming peptide nucleic acids (PNAs) loaded into biodegradable nanoparticles (NPs) in combination with donor DNAs as reagents for correcting mutations associated with genetic diseases including CF.
View Article and Find Full Text PDFPTI-801 (posenacaftor) shares a common mechanism with VX-445 (elexacaftor) to rescue p.Phe508del-CFTR.
Eur J Pharmacol
March 2024
Biosystems & Integrative Sciences Institute (BioISI), Faculty of Sciences, University of Lisbon, 1749-016, Lisbon, Portugal. Electronic address:
The deletion of a phenylalanine at position 508 (p.Phe508del) in the CFTR anion channel is the most prevalent variant in people with Cystic Fibrosis (CF). This variant impairs folding and stability of the CF transmembrane conductance regulator (CFTR) protein, resulting in its defective trafficking and premature degradation.
View Article and Find Full Text PDFPutting bicarbonate on the spot: pharmacological insights for CFTR correction in the airway epithelium.
Front Pharmacol
December 2023
INSERM U1151, Institut Necker Enfants Malades, Paris, France.
Cystic fibrosis (CF) is caused by defective Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) proteins. CFTR controls chloride (Cl) and bicarbonate (HCO ) transport into the Airway Surface Liquid (ASL). We investigated the impact of F508del-CFTR correction on HCO secretion by studying transepithelial HCO fluxes.
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