4th Medicinal & Biological Chemistry Ireland conference: Putting the CAP on ENaC: Targeting serine proteases to regulate airways hydration and mucociliary clearance in chronic airways diseases

Description

Chronic airways diseases. such as cystic fibrosis (CF), are associated with significant airways dehydration that contributes to mucus obstruction and impaired mucociliary clearance (MCC). In normal airways an optimal volume of airways surface liquid (ASL) is regulated by the cystic fibrosis transmembrane conductance regulator (CFTR) working in concert with the epithelial sodium channel (ENaC), to balance Cl- secretion with Na+ absorption, respectively. In CF, mutations in CFTR, coupled with a dysregulation of ENaC, thickens airways secretions leading to devastating cycles of infection and inflammation and irreversible tissue injury. A major development in recent years has been the approval of CFTR modulator therapies which have helped stall the progressive decline in lung function, characteristic of this disease. Other therapeutic strategies are however, urgently required for those who have no access to these drugs and for the 10% of people with CF worldwide who have nonsense mutations, and thus are non-responsive to CFTR modulation. Inhibition of ENaC offers an attractive, mutation-agnostic approach to treatment that would be suitable for all people with CF, as well as those suffering from other chronic airways diseases such as chronic obstructive pulmonary disease (COPD).

ENaC is activated by the proteolytic cleavage of its subunits , each of which includes two membrane-spanning domains connected by a large extracellular loop. The channel activating proteases (CAPs) predominantly belong to the trypsin-like family of serine proteases although neutrophil elastase can induce activation of ENaC subsequent to pre-processing by the proprotein convertase, furin. The presentation will discuss how broad-spectrum inhibition of putative CAPs, to include prostasin and matriptase, and the selective inhibition of furin, diminishes ENaC-mediated Na+ absorption in CF primary human airway epithelial cells leading to an increase in airways hydration and restoration of MCC. In particular, selective furin inhibition holds significant promise as a treatment for both CF and COPD.

Period	16 Jul 2025
Event title	4th Medicinal & Biological Chemistry Ireland conference
Event type	Conference
Location	Belfast, United KingdomShow on map
Degree of Recognition	International