Inhibition of ENaC activity by novel peptide trypsin-like inhibitors derived from amphibian skin secretions

E.L. Carroll, L.E.J. Douglas, J.A. Reihill, M. Zhou, T. Chen, L.P. McGarvey, F.T. Lundy, M.A. Hollywood, A. Crilly, J.C. Lockhart, S.L. Martin

Research output: Contribution to journalMeeting Abstract

Abstract

ENaC is activated by trypsin-like (TL) channel activating proteases
(CAPs), inhibition of which in cystic fibrosis has been shown to increase airways surface liquid and normalise mucociliary clearance (MCC)1. These proteases have potential to be therapeutic targets in other chronic airways diseases. This study investigated the ability of natural peptide TL inhibitors, derived from amphibian skin secretions, to inactivate ENaC via CAP inhibition.

Initial screening of the frog peptides was conducted using FRT cells stably transfected with ENaC and changes in fluorescence intensity (FLIPR) utilised to measure ENaC activity. Second round testing was performed using primary differentiated human airway epithelial cells (hAECs) by measurement of IEQ (equivalent short-circuit current) (TECC-24; EP Devices).

FLIPR revealed that all of the frog peptides significantly inhibited
ENaC, particularly QUB-1916 which elicited almost immediate,
complete channel inhibition. Different trends were observed when
the peptides were tested on hAECs using short-circuit current,
with other peptides demonstrating superior ENaC inhibition compared to QUB-1916. Initial profiling indicates a differential protease expression pattern between cell types which may underlie this discrepancy.

These findings highlight the importance of direct testing of channel activity using hAECs. Potential lead compounds are currently being evaluated for efficacy in airway hydration and MCC
studies.
Original languageEnglish
Pages (from-to)S250-S251
Number of pages2
JournalIrish Journal of Medical Science
Volume187
Issue numberSupplement 8
DOIs
Publication statusPublished - Aug 2018

Keywords

  • COPD
  • BREATH
  • ENaC
  • interreg va
  • SEUPB
  • trypsin

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  • Activities

    • 1 Participation in workshop, seminar, course
    • 1 Types of Public engagement and outreach - Public lecture/debate/seminar
    • 1 Oral presentation

    Cross Party Group on Lung Health, Scottish Parliament (attending member)

    John Lockhart (Invited speaker)

    12 Jun 2018

    Activity: Participating in or organising an eventParticipation in workshop, seminar, course

    BREATH Ayrshire Stakeholder Event

    John Lockhart (Speaker), , Gary Litherland (Speaker), , Anur Guhan (Speaker), , Lorcan McGarvey (Speaker), , Keith Thornbury (Speaker), & Iain McLellan (Speaker)

    22 Aug 2018

    Activity: Talk or presentationOral presentation

    BREATH Dumfries and Galloway Launch Event

    Anne Crilly (Participant), , Gary Litherland (Speaker), & John Lockhart (Speaker)

    Aug 2017

    Activity: OtherTypes of Public engagement and outreach - Public lecture/debate/seminar

    Press / Media

    Scientists honoured for their bid to ease lung disease misery

    John Lockhart, Gary Litherland, Anne Crilly, Carl Goodyear, Lorraine Martin, Keith Thornbury, Mark Hollywood, Gerard Sergeant, Fionnuala Lundy & Lorcan McGarvey

    9/03/18

    1 item of Media coverage

    Press/Media: Research

    Cite this

    Carroll, E. L., Douglas, L. E. J., Reihill, J. A., Zhou, M., Chen, T., McGarvey, L. P., Lundy, F. T., Hollywood, M. A., Crilly, A., Lockhart, J. C., & Martin, S. L. (2018). Inhibition of ENaC activity by novel peptide trypsin-like inhibitors derived from amphibian skin secretions. Irish Journal of Medical Science, 187(Supplement 8), S250-S251. https://doi.org/10.1007/s11845-018-1898-7