Chronic obstructive pulmonary disease (COPD) is associated with two major clinical phenotypes; chronic bronchitis (CB) and emphysema. Impaired mucociliary clearance is a feature of CB which is influenced by Cl- secretion by the cystic fibrosis transmembrane conductance regulator (CFTR) and Na+ absorption by the epithelial sodium channel (ENaC). Furin, a cellular proprotein convertase, is a key proteolytic activator of ENaC. We have recently shown highly selective furin inhibition to inhibit ENaC and improve mucociliary transport (MCT) in cystic fibrosis (CF) airways cells (Douglas et al (2022) Cell Chem. Biol. 29(6):947-957). As mutated CFTR results in CF lung disease that shares phenotypic characteristics with CB, the aim of this study was to investigate the effect of a novel, highly potent, selective furin inhibitor, BOS-857 on ENaC activity and MCT in COPD. This study also aimed to determine whether BOS-857 used in combination with CFTR potentiator, ivacaftor would provide additional benefit.

BOS-857 treatment of COPD HBECs significantly reduced ENaC-mediated Na+ absorption by 80% after a 48h exposure and prevented subsequent cell-surface activation of ENaC by neutrophil elastase. Treatment of COPD HBECs with either BOS-857 or VX-770 alone improved MCT rates. When COPD HBECs were treated with a combination of BOS-857 and VX-770, significant improvements in MCT rate over VX-770 alone were observed.

These studies support highly selective furin inhibition as a therapeutic approach for COPD and suggest that further therapeutic benefit may also be derived by combining furin inhibition with a CFTR potentiator.