title: Benzo(c)quinolizinium drugs inhibit degradation of Delta F508-CFTR cytoplasmic domain.
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.
authors.affiliation: Department of Medical Biochemistry, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Fiona L L
authors.initials: FL
authors.lastname: Stratford
authors.forename: Malcolm M C
authors.initials: MM
authors.lastname: Pereira
authors.forename: Frederic
authors.initials: F
authors.lastname: Becq
authors.forename: Margaret A
authors.initials: MA
authors.lastname: McPherson
authors.forename: Robert L
authors.initials: RL
authors.lastname: Dormer
mesh_terms: D000818:Animals; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000737:chemistry; D007700:Kinetics; D011480:Protease Inhibitors / Q000494:pharmacology; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011807:Quinolizines / Q000494:pharmacology*; D011817:Rabbits; D012156:Reticulocytes / Q000378:metabolism; D017384:Sequence Deletion; D014158:Transcription, Genetic
chemical_list: C439425:5-butyl-6-hydroxy-10-chlorobenzo(c)quinolizinium chloride; C451901:6-hydroxy-10-chlorobenzo(c)quinolizinium; D011480:Protease Inhibitors; D011807:Quinolizines; D019005:Cystic Fibrosis Transmembrane Conductance Regulator