The development of novel strategies to modulate epithelial sodium channel (ENaC) activity in chronic obstructive pulmonary disease (COPD)

Inhibition of ENaC function in the airways has become an attractive therapeutic strategy to counteract airway surface dehydration and defective MCC. Thus, the overarching aim of this research was to investigate the potential of two novel strategies to modulate ENaC activity. <br><br>A CAP inhibitor-based approach utilising natural peptide-based inhibitors, derived from amphibian skin secretions, revealed two lead compounds - QUB- 1916 and QUB-2136.

Both peptides were found to exhibit potent low-micromolar or nanomolar inhibitory activity against human airway trypsin-like (HAT) protease, matriptase, and prostasin. QUB-2136 was capable of inhibiting amiloride short-circuit current to a greater extent and for a longer period of time when compared to QUB-1916. However, further evaluation of QUB-2136 indicated that structural modifications would be necessary in order for this peptide to have utility in functional ASL height, MCC and in vivo studies.<br><br>A second genomic approach investigated the ability of the QUB-patented RALA peptide drug delivery system to transport an αENaC small interfering RNA (siRNA) cargo into primary bronchial epithelial cells (PBECs).