Development of a Novel Backbone Cyclic Peptide Inhibitor of the Innate Immune TLR/IL1R Signaling Protein MyD88
| العنوان: | Development of a Novel Backbone Cyclic Peptide Inhibitor of the Innate Immune TLR/IL1R Signaling Protein MyD88 |
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| المؤلفون: | Ibrahim Kassis, Gabriel Nussbaum, Chaim Gilon, Adi Schumacher, Joseph Fanous, Amnon Hoffman, Alaa Talhami, Shira Dishon, Dimitrios Karussis |
| المصدر: | Scientific Reports Scientific Reports, Vol 8, Iss 1, Pp 1-12 (2018) |
| بيانات النشر: | Springer Science and Business Media LLC, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Encephalomyelitis, Autoimmune, Experimental, Anti-Inflammatory Agents, lcsh:Medicine, Inflammation, Peptide, Peptides, Cyclic, Article, Mice, 03 medical and health sciences, medicine, Animals, Humans, lcsh:Science, chemistry.chemical_classification, Binding Sites, Multidisciplinary, Innate immune system, lcsh:R, Toll-Like Receptors, NF-kappa B, Receptors, Interleukin-1, Signal transducing adaptor protein, Cyclic peptide, Protein mimetic, Cell biology, Mice, Inbred C57BL, HEK293 Cells, RAW 264.7 Cells, 030104 developmental biology, chemistry, Myeloid Differentiation Factor 88, lcsh:Q, Female, medicine.symptom, Decoy, Function (biology), HeLa Cells, Protein Binding |
| الوصف: | MyD88 is a cytoplasmic adaptor protein that plays a central role in signaling downstream of the TLRs and the IL1R superfamily. We previously demonstrated that MyD88 plays a critical role in EAE, the murine model of multiple sclerosis, and showed that the MyD88 BB-loop decoy peptide RDVLPGT ameliorates EAE. We now designed and screened a library of backbone cyclized peptides based on the linear BB loop peptide, to identify a metabolically stable inhibitor of MyD88 that retains the binding properties of the linear peptide. We identified a novel cyclic peptide protein mimetic that inhibits inflammatory responses to TLR ligands, and NFκB activation in response to IL-1 activation. The inhibitor, c(MyD 4-4), is metabolically stable in comparison to the linear peptide, blocks MyD88 in a specific manner, and inhibits MyD88 function by preventing MyD88 dimerization. Finally, treatment of mice with c(MyD 4-4) reduced the severity of clinical disease in the murine EAE model of multiple sclerosis. Thus, modulation of MyD88-dependent signaling using c(MyD 4-4) is a potential therapeutic strategy to lower innate immune inflammation in autoimmune CNS disease. |
| تدمد: | 2045-2322 |
| DOI: | 10.1038/s41598-018-27773-8 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2f6b432970e784eda88c70d9e6da252a https://doi.org/10.1038/s41598-018-27773-8 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....2f6b432970e784eda88c70d9e6da252a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20452322 |
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| DOI: | 10.1038/s41598-018-27773-8 |