VX-809 and related corrector compounds exhibit secondary activity stabilizing active F508del-CFTR after its partial rescue to the cell surface

Paul D.W. Eckford, Mohabir Ramjeesingh, Steven Molinski, Stan Pasyk, Johanna F. Dekkers, Canhui Li, Saumel Ahmadi, Wan Ip, Timothy E. Chung, Kai Du, Herman Yeger, Jeffrey Beekman, Tanja Gonska, Christine E. Bear

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

78 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)666-678
Aantal pagina's13
TijdschriftChemistry and Biology
Volume21
Nummer van het tijdschrift5
DOI's
StatusGepubliceerd - 22 mei 2014
Extern gepubliceerdJa

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