Macrocycle-stabilization of its interaction with 14-3-3 increases plasma membrane localization and activity of CFTR

Loes M. Stevers, Madita Wolter, Graeme W. Carlile, Dwight Macdonald, Luc Richard, Frank Gielkens, John W. Hanrahan, David Y. Thomas, Sai Kumar Chakka, Mark L. Peterson, Helmut Thomas, Luc Brunsveld and Christian Ottmann ()
Additional contact information
Loes M. Stevers: Eindhoven University of Technology
Madita Wolter: Eindhoven University of Technology
Graeme W. Carlile: McGill University
Dwight Macdonald: Cyclenium Pharma Inc., 7171 rue Frederick Banting
Luc Richard: Cyclenium Pharma Inc., 7171 rue Frederick Banting
Frank Gielkens: Eindhoven University of Technology
John W. Hanrahan: McGill University
David Y. Thomas: McGill University
Sai Kumar Chakka: Cyclenium Pharma Inc., 7171 rue Frederick Banting
Mark L. Peterson: Cyclenium Pharma Inc., 7171 rue Frederick Banting
Helmut Thomas: Cyclenium Pharma Inc., 7171 rue Frederick Banting
Luc Brunsveld: Eindhoven University of Technology
Christian Ottmann: Eindhoven University of Technology

Nature Communications, 2022, vol. 13, issue 1, 1-9

Abstract: Abstract Impaired activity of the chloride channel CFTR is the cause of cystic fibrosis. 14-3-3 proteins have been shown to stabilize CFTR and increase its biogenesis and activity. Here, we report the identification and mechanism of action of a macrocycle stabilizing the 14-3-3/CFTR complex. This molecule rescues plasma membrane localization and chloride transport of F508del-CFTR and works additively with the CFTR pharmacological chaperone corrector lumacaftor (VX-809) and the triple combination Trikafta®. This macrocycle is a useful tool to study the CFTR/14-3-3 interaction and the potential of molecular glues in cystic fibrosis therapeutics.

Date: 2022
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DOI: 10.1038/s41467-022-31206-6

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