Benzo(c)quinolizinium drugs inhibit degradation of Delta F508-CFTR cytoplasmic domain

Biochem Biophys Res Commun. 2003 Jan 10;300(2):524-30. doi: 10.1016/s0006-291x(02)02883-8.


Proteins comprising the first nucleotide-binding- and R-domains of wild-type and Delta F508 cystic fibrosis transmembrane conductance regulator (CFTR) have been synthesised by in vitro transcription/translation. The kinetics and extent of degradation of wild-type and Delta F508 cytoplasmic domain proteins in rabbit reticulocyte lysates, in which proteasome activity was inhibited, were similar, with a half-life of approximately 4h. The results show for the first time, that the benzo(c)quinolizinium compounds, MPB-07 and MPB-91, selectively inhibit degradation of the Delta F508 cytoplasmic domain protein. Studies using protease inhibitors demonstrated that both Delta F508 and wild-type proteins are substrates for cysteine proteases. The studies provide evidence that benzo(c)quinolizinium compounds protect a proteolytic cleavage site by direct binding to the first cytoplasmic domain of Delta F508-CFTR and this is a likely mechanism for increasing Delta F508-CFTR trafficking in intact cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cystic Fibrosis Transmembrane Conductance Regulator / chemistry*
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • Cytoplasm / chemistry
  • Kinetics
  • Protease Inhibitors / pharmacology
  • Protein Biosynthesis
  • Protein Structure, Tertiary
  • Protein Transport
  • Quinolizines / pharmacology*
  • Rabbits
  • Reticulocytes / metabolism
  • Sequence Deletion
  • Transcription, Genetic


  • 5-butyl-6-hydroxy-10-chlorobenzo(c)quinolizinium chloride
  • 6-hydroxy-10-chlorobenzo(c)quinolizinium
  • Protease Inhibitors
  • Quinolizines
  • Cystic Fibrosis Transmembrane Conductance Regulator