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

Nat Commun. 2022 Jun 23;13(1):3586. doi: 10.1038/s41467-022-31206-6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminophenols / metabolism
  • Aminopyridines / metabolism
  • Aminopyridines / pharmacology
  • Cell Membrane / metabolism
  • Cystic Fibrosis Transmembrane Conductance Regulator* / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator* / metabolism
  • Cystic Fibrosis* / drug therapy
  • Cystic Fibrosis* / metabolism
  • Humans
  • Mutation

Substances

  • Aminophenols
  • Aminopyridines
  • CFTR protein, human
  • Cystic Fibrosis Transmembrane Conductance Regulator

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