Proteins comprising the first nucleotide-binding- and R-domains of wild-type and DeltaF508 cystic fibrosis transmembrane conductance regulator (CFTR) have been synthesised by in vitro transcription/translation. The kinetics and extent of degradation of wild-type and DeltaF508 cytoplasmic domain proteins in rabbit reticulocyte lysates, in which proteasome activity was inhibited, were similar, with a half-life of approximately 4 h. The results show for the first time, that the benzo(c)quinolizinium compounds, MPB-07 and MPB-91, selectively inhibit degradation of the DeltaF508 cytoplasmic domain protein. Studies using protease inhibitors demonstrated. that both DeltaF508 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 DeltaF508-CFTR and this is a likely mechanism for increasing DeltaF508-CFTR trafficking in intact cells. (C) 2002 Elsevier Science (USA). All rights reserved.