Macrocycle-stabilization of its interaction with 14-3-3 increases plasma membrane localization and activity of CFTR.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 35739107.
- Also identified by DOI 10.1038/s41467-022-31206-6 and PMC identifier 9226124.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Cystic Fibrosis
- Cystic Fibrosis Transmembrane Conductance Regulator