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Updated: May 1, 2026

Functional Reconstitution and Channel Activity Measurements of Purified Wildtype and Mutant CFTR Protein
Published on: March 9, 2015
VX-809 and related corrector compounds exhibit secondary activity stabilizing active F508del-CFTR after its partial
Paul D W Eckford1, Mohabir Ramjeesingh1, Steven Molinski1
1Programme of Molecular Structure and Function, Research Institute, Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 1X8, Canada.
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.
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