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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 B, 2022. "Macrocycle-stabilization of its interaction with 14-3-3 increases plasma membrane localization and activity of CFTR," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31206-6
    DOI: 10.1038/s41467-022-31206-6
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