Targeting Trypsin-Like Proteases: A Mechanism to Restore Mucociliary Function in Cystic Fibrosis Airways

Research output: Contribution to conferencePaper

Abstract

Dehydration of the airway surface liquid (ASL) and the resultant decline in function of the mucociliary escalator in cystic fibrosis airways is largely underpinned by the excessive flux of Na+ and water though ENaC. Proteolysis of the endogenous  and  subunits of epithelial sodium channels (ENaC) by channel activating proteases (CAPS) is the key regulatory mechanism for channel activation. Recent reports highlight that (1) CFTR (cystic fibrosis transmembrane conductance regulator) normally protects ENaC from the action of proteases and (2) a stark imbalance in proteases/protease inhibitor levels in CF airway cultures favour activation of normally inactive ENaC. The current study examines the potential therapeutic benefit of CAPS/ENaC inhibition in CF airways.
Our group has developed a panel of active-site directed affinity-based probes which target and inhibit trypsin-like proteases (potential CAPS); including the broad-spectrum inhibitor QUB-TL1. We have utilised this compound to interrogate the impact of trypsin-like protease inhibition on ENaC activity in differentiated primary airway epithelial cell cultures.
Electrophysiological data demonstrate QUB-TL1 selectively and irreversibly binds to extracellularly located trypsin-like proteases resulting in impaired ENaC-mediated Na+ transport. Visualisation of ENaC at the apical surface compartment of primary airway epithelial cells shows a large reduction in a low molecular weight (processed and active) form of ENaC, which was found to be abundant in untreated CF cultures. Consistent with the reduction in ENaC activity observed, QUB-TL1 treatment was subsequently shown to increase ASL height (performed in collaboration with Royal College of Surgeons in Ireland).
Our results are consistent with the hypothesis that targeting the CAPS-ENaC signalling axis may restore the depleted ASL seen in CF airways.
Original languageEnglish
Publication statusPublished - 15 Apr 2013
EventProteinase 2013: 8th RSC / SCI symposium on Proteinase Inhibitor Design - Novartis Campus, Basel, Switzerland
Duration: 15 Apr 201316 Apr 2013

Conference

ConferenceProteinase 2013: 8th RSC / SCI symposium on Proteinase Inhibitor Design
CountrySwitzerland
CityBasel
Period15/04/201316/04/2013

Keywords

  • channel activating proteases
  • ENaC
  • Cystic fibrosis
  • airways surface liquid
  • mucocilary clearance
  • inhibitors

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