title: VX-809 and related corrector compounds exhibit secondary activity stabilizing active F508del-CFTR after its partial rescue to the cell surface.
abstract: The 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.
authors.affiliation: Programme of Molecular Structure and Function, Research Institute, Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 1X8, Canada.
authors.forename: Paul D W
authors.initials: PD
authors.lastname: Eckford
authors.affiliation: Programme of Molecular Structure and Function, Research Institute, Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 1X8, Canada.
authors.forename: Mohabir
authors.initials: M
authors.lastname: Ramjeesingh
authors.affiliation: Programme of Molecular Structure and Function, Research Institute, Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 1X8, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Molinski
authors.affiliation: Programme of Molecular Structure and Function, Research Institute, Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 1X8, Canada.
authors.forename: Stan
authors.initials: S
authors.lastname: Pasyk
authors.affiliation: Department of Pediatric Pulmonology and Laboratory of Translational Immunology, University Medical Center, WKZ Utrecht, 3584 Utrecht, the Netherlands.
authors.forename: Johanna F
authors.initials: JF
authors.lastname: Dekkers
authors.affiliation: Programme of Molecular Structure and Function, Research Institute, Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 1X8, Canada.
authors.forename: Canhui
authors.initials: C
authors.lastname: Li
authors.affiliation: Programme of Molecular Structure and Function, Research Institute, Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 1X8, Canada.
authors.forename: Saumel
authors.initials: S
authors.lastname: Ahmadi
authors.affiliation: Programme of Physiology & Experimental Medicine, Research Institute, Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 1X8, Canada.
authors.forename: Wan
authors.initials: W
authors.lastname: Ip
authors.affiliation: Programme of Molecular Structure and Function, Research Institute, Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 1X8, Canada.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Chung
authors.affiliation: Programme in Developmental and Stem Cell Biology, Research Institute, Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 1X8, Canada.
authors.forename: Kai
authors.initials: K
authors.lastname: Du
authors.affiliation: Programme in Developmental and Stem Cell Biology, Research Institute, Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 1X8, Canada.
authors.forename: Herman
authors.initials: H
authors.lastname: Yeger
authors.affiliation: Department of Pediatric Pulmonology and Laboratory of Translational Immunology, University Medical Center, WKZ Utrecht, 3584 Utrecht, the Netherlands.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Beekman
authors.affiliation: Programme of Physiology & Experimental Medicine, Research Institute, Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 1X8, Canada.
authors.forename: Tanja
authors.initials: T
authors.lastname: Gonska
authors.affiliation: Programme of Molecular Structure and Function, Research Institute, Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 1X8, Canada. Electronic address: bear@sickkids.ca.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Bear
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D006224:Cricetinae; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D055550:Protein Stability / Q000187:drug effects; D013329:Structure-Activity Relationship; D013499:Surface Properties
chemical_list: D000631:Aminopyridines; D052117:Benzodioxoles; C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C569105:lumacaftor