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

Stevers, L. M.; Wolter, M.; Carlile, G.; Macdonald, D.; Richard, L.; Gielkens, F.; Thomas, D.; Chakka, S. K.; Peterson, M. L.; Thomas, H.; Brunsveld, L.; Ottmann, C.

doi:10.1101/2022.01.03.473871

bioRxiv · 10.1101/2022.01.03.473871

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

Stevers, L. M.·Wolter, M.·Carlile, G.·Macdonald, D.·Richard, L.·Gielkens, F.·Thomas, D.·Chakka, S. K.·Peterson, M. L.·Thomas, H.·Brunsveld, L.·Ottmann, C.

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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, a first-in-class molecular glue. This molecule rescues plasma membrane localization and chloride transport of F508del-CFTR and works additively with the CFTR pharmacological chaperone corrector lumacaftor (VX-809).

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Stevers, L. M., Wolter, M., Carlile, G., Macdonald, D., Richard, L., Gielkens, F., Thomas, D., Chakka, S. K., Peterson, M. L., Thomas, H., Brunsveld, L., Ottmann, C.. 2022-01-03. Macrocycle-stabilization of its interaction with 14-3-3 increases plasma membrane localization and activity of CFTR. https://doi.org/10.1101/2022.01.03.473871

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