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

      Biochemical and Biophysical Research Communications
      Animals, Cystic Fibrosis Transmembrane Conductance Regulator, chemistry, genetics, metabolism, Cytoplasm, Kinetics, Protease Inhibitors, pharmacology, Protein Biosynthesis, Protein Structure, Tertiary, Protein Transport, Quinolizines, Rabbits, Reticulocytes, Sequence Deletion, Transcription, Genetic

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          Abstract

          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.

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