Channel activating proteases: molecular targets for correction of sodium channel dysfunction in cystic fibrosis airways disease

Previous work has shown that QUB-TL1, an active site directed inhibitor of trypsin and trypsin-like enzymes, reduces ENaC-mediated sodium absorption from the surface of airway epithelial cells in CF, which was associated with improved mucociliary clearance due to a concomitant increase in airways hydration. The initial aim of this project, therefore, was to synthesize and evaluate three novel inhibitors of trypsin-like channel activating proteases to determine their effect on inflammatory signaling via PAR-2 and also on ENaC activity in CF airway epithelial cells (AECs).

Further, two highly selective and potent furin inhibitors, BOS-981 and BOS-318 were characterised, with the aim of determining whether selective inhibition of furin has the potential to reduce ENaC-mediated sodium transport and improve airways hydration. The effect of BOS-981 and BOS-318 on inflammatory signalling and TGF-β secretion in CF AECs was also investigated.<br><br><i>Thesis embargoed 31 July 2024</i>.