Identification of small‐molecule elastase inhibitors as antagonists of IL‐36 cytokine activation
2018
Sullivan, Graeme P. | Davidovich, Pavel B. | Sura‐Trueba, Sylvia | Belotcerkovskaya, Ekaterina | Henry, Conor M. | Clancy, Danielle M. | Zinoveva, Anna | Mametnabiev, Tazhir | Garabadzhiu, Alexander V. | Martin, Seamus J.
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.
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