1. Academic Validation
  2. Identification of small-molecule elastase inhibitors as antagonists of IL-36 cytokine activation

Identification of small-molecule elastase inhibitors as antagonists of IL-36 cytokine activation

  • FEBS Open Bio. 2018 Mar 25;8(5):751-763. doi: 10.1002/2211-5463.12406.
Graeme P Sullivan 1 Pavel B Davidovich 1 2 Sylvia Sura-Trueba 2 Ekaterina Belotcerkovskaya 2 Conor M Henry 1 Danielle M Clancy 1 Anna Zinoveva 1 2 Tazhir Mametnabiev 2 Alexander V Garabadzhiu 2 Seamus J Martin 1 2
Affiliations

Affiliations

  • 1 Molecular Cell Biology Laboratory Department of Genetics The Smurfit Institute Trinity College Dublin 2 Ireland.
  • 2 Cellular Biotechnology Laboratory Saint-Petersburg State Institute of Technology Russia.
Abstract

IL-1 family cytokines act as apical initiators of inflammation in many settings and can promote the production of a battery of inflammatory cytokines, chemokines and other inflammatory mediators in diverse cell types. IL-36α, IL-36β and IL-36γ, which belong to the extended IL-1 family, have been implicated as key initiators of skin inflammation in psoriasis. IL-36γ is highly upregulated in lesional skin from psoriatic individuals, and heritable mutations in the natural IL-36 receptor antagonist result in a severe form of psoriasis. IL-36 family cytokines are initially expressed as inactive precursors that require proteolytic processing for activation. The neutrophil granule-derived protease Elastase proteolytically processes and activates IL-36α and IL-36γ, increasing their biological activity ~ 500-fold, and also robustly activates IL-1α and IL-33 through limited proteolytic processing. Consequently, inhibitors of Elastase activity may have potential as anti-inflammatory agents through antagonizing the activation of multiple IL-1 family cytokines. Using in silico screening approaches, we have identified small-molecule inhibitors of Elastase that can antagonize activation of IL-36γ by the latter protease. The compounds reported herein may have utility as lead compounds for the development of inhibitors of elastase-mediated activation of IL-36 and other IL-1 family cytokines in inflammatory conditions, such as psoriasis.

Keywords

IL‐1 family; IL‐36; elastase; inflammation; protease; psoriasis.

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