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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.
Eckford, Paul D W; Ramjeesingh, Mohabir; Molinski, Steven; Pasyk, Stan; Dekkers, Johanna F; Li, Canhui; Ahmadi, Saumel; Ip, Wan; Chung, Timothy E; Du, Kai; Yeger, Herman; Beekman, Jeffrey; Gonska, Tanja; Bear, Christine E.
Afiliación
  • Eckford PD; 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.
  • Ramjeesingh M; 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.
  • Molinski S; 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.
  • Pasyk S; 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.
  • Dekkers JF; Department of Pediatric Pulmonology and Laboratory of Translational Immunology, University Medical Center, WKZ Utrecht, 3584 Utrecht, the Netherlands.
  • Li C; 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.
  • Ahmadi S; 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.
  • Ip W; Programme of Physiology & Experimental Medicine, Research Institute, Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 1X8, Canada.
  • Chung TE; 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.
  • Du K; 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.
  • Yeger H; 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.
  • Beekman J; Department of Pediatric Pulmonology and Laboratory of Translational Immunology, University Medical Center, WKZ Utrecht, 3584 Utrecht, the Netherlands.
  • Gonska T; Programme of Physiology & Experimental Medicine, Research Institute, Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 1X8, Canada.
  • Bear CE; 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.
Chem Biol ; 21(5): 666-78, 2014 May 22.
Article en En | MEDLINE | ID: mdl-24726831
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Membrana Celular / Regulador de Conductancia de Transmembrana de Fibrosis Quística / Fibrosis Quística / Benzodioxoles / Aminopiridinas Límite: Animals / Humans Idioma: En Revista: Chem Biol Asunto de la revista: BIOLOGIA / BIOQUIMICA / QUIMICA Año: 2014 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Membrana Celular / Regulador de Conductancia de Transmembrana de Fibrosis Quística / Fibrosis Quística / Benzodioxoles / Aminopiridinas Límite: Animals / Humans Idioma: En Revista: Chem Biol Asunto de la revista: BIOLOGIA / BIOQUIMICA / QUIMICA Año: 2014 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos