Development of a novel backbone cyclic peptide inhibitor of the innate immune TLR/IL1R signaling protein MyD88

Shira Dishon, Adi Schumacher, Joseph Fanous, Alaa Talhami, Ibrahim Kassis, Dimitrios Karussis, Chaim Gilon, Amnon Hoffman, Gabriel Nussbaum*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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 languageAmerican English
Article number9476
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - 1 Dec 2018

Bibliographical note

Publisher Copyright:
© 2018 The Author(s).

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