Identification of small‐molecule elastase inhibitors as antagonists of IL‐36 cytokine activation
| العنوان: | Identification of small‐molecule elastase inhibitors as antagonists of IL‐36 cytokine activation |
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| المؤلفون: | Tazhir Mametnabiev, Sylvia Sura-Trueba, Ekaterina Belotcerkovskaya, Conor M. Henry, Graeme P. Sullivan, Pavel B. Davidovich, Danielle M. Clancy, Anna Zinoveva, Seamus J. Martin, A. V. Garabadzhiu |
| المصدر: | FEBS Open Bio FEBS OPEN BIO |
| بيانات النشر: | Wiley, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Chemokine, medicine.drug_class, medicine.medical_treatment, NF-KAPPA-B, Inflammation, IL‐36, IL‐1 family, ALPHA-1-ANTITRYPSIN DEFICIENCY, General Biochemistry, Genetics and Molecular Biology, IL-1 family, Proinflammatory cytokine, 03 medical and health sciences, 0302 clinical medicine, Psoriasis, Medicine and Health Sciences, medicine, elastase, IL-36-GAMMA, Research Articles, REGULATORS, PSORIASIS, Protease, biology, Chemistry, Elastase, FAMILY CYTOKINES, Biology and Life Sciences, protease, Biological activity, psoriasis, medicine.disease, Receptor antagonist, DERMATITIS, AGONIST, IL-36, 030104 developmental biology, inflammation, 030220 oncology & carcinogenesis, Cancer research, biology.protein, LIGANDS, medicine.symptom, MEMBERS, Research Article |
| الوصف: | 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-36 alpha, IL-36 beta and IL-36 gamma, which belong to the extended IL-1 family, have been implicated as key initiators of skin inflammation in psoriasis. IL-36 gamma 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-36 alpha and IL-36 gamma, increasing their biological activity similar to 500-fold, and also robustly activates IL-1 alpha 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-36 gamma 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. |
| وصف الملف: | application/pdf |
| تدمد: | 2211-5463 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6188b9b11c406f595ab9977b2e216165Test https://doi.org/10.1002/2211-5463.12406Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....6188b9b11c406f595ab9977b2e216165 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22115463 |
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