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VX-809 and Related Corrector Compounds Exhibit Secondary Activity Stabilizing Active F508del-CFTR after Its Partial Rescue to the Cell Surface
- Source :
- Chemistry & Biology. (5):666-678
- Publisher :
- Elsevier Ltd.
-
Abstract
- SummaryThe most common mutation causing cystic fibrosis (CF), F508del, impairs conformational maturation of CF transmembrane conductance regulator (CFTR), thereby reducing its functional expression on the surface of epithelia. Corrector compounds including C18 (VRT-534) and VX-809 have been shown to partially rescue misfolding of F508del-CFTR and to enhance its maturation and forward trafficking to the cell surface. Now, we show that there is an additional action conferred by these compounds beyond their role in improving the biosynthetic assembly. In vitro studies show that these compounds bind directly to the metastable, full-length F508del-CFTR channel. Cell culture and patient tissue-based assays confirm that in addition to their cotranslational effect on folding, certain corrector compounds bind to the full-length F508del-CFTR after its partial rescue to the cell surface to enhance its function. These findings may inform the development of alternative compounds with improved therapeutic efficacy.
- Subjects :
- Cystic Fibrosis
Surface Properties
Stereochemistry
Clinical Biochemistry
Cell
Regulator
Aminopyridines
Cystic Fibrosis Transmembrane Conductance Regulator
Biology
medicine.disease_cause
Biochemistry
Cystic fibrosis
Structure-Activity Relationship
Cricetinae
Drug Discovery
F508del cftr
medicine
Animals
Humans
Benzodioxoles
Molecular Biology
Cells, Cultured
Pharmacology
Mutation
Dose-Response Relationship, Drug
Protein Stability
Cell Membrane
General Medicine
medicine.disease
Transmembrane protein
3. Good health
Cell biology
HEK293 Cells
medicine.anatomical_structure
Cell culture
Molecular Medicine
Function (biology)
Subjects
Details
- Language :
- English
- ISSN :
- 10745521
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Chemistry & Biology
- Accession number :
- edsair.doi.dedup.....92253ef89726787fcad9d37c2b93c87b
- Full Text :
- https://doi.org/10.1016/j.chembiol.2014.02.021