Channel activating proteases

: Molecular targets for correction of sodium channel dysfunction in cystic fibrosis airways disease

Abstract

Cystic fibrosis (CF) is an autosomal recessive disease, caused by mutations in the gene which codes for the CF transmembrane conductance regulator (CFTR). Mutations in CFTR cause multi-organ dysfunction, including in the lungs, pancreas, gastro-intestinal system and the reproductive system. However, lung disease is the major cause of morbidity and mortality in people with CF PWCF. CF lung disease is characterised by hyper-susceptibility to infection coupled with mucus obstruction, exaggerated inflammatory responses and resulting pulmonary damage and decline. Dysregulation of ENaC, secondary to the loss of functional CFTR in CF, leads to increased Na+ absorption which contributes to airways dehydration, thickened mucus, impaired mucociliary clearance and is thought to be a major contributor to the pathogenesis of lung 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.

Thesis embargoed 31 July 2024.

Date of Award	Jul 2019
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Northern Ireland Department for the Economy & Medical Research Council
Supervisor	Lorraine Martin (Supervisor) & Irina Tikhonova (Supervisor)