Abstract
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.
Original language | American English |
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Article number | 9476 |
Journal | Scientific Reports |
Volume | 8 |
Issue number | 1 |
DOIs | |
State | Published - 1 Dec 2018 |
Bibliographical note
Funding Information:This work was supported by grants from the Israeli Ministry of Science and Technology, and the Ministry of Economy and Industry. We thank Dr. Luba Eli-Berchoier for technical assistance with many aspects of the work and the STEP Foundation for a student stipend to SD.
Publisher Copyright:
© 2018 The Author(s).