Unknown

Dataset Information

0

Development of a Novel Backbone Cyclic Peptide Inhibitor of the Innate Immune TLR/IL1R Signaling Protein MyD88.


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 NF?B 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.

SUBMITTER: Dishon S 

PROVIDER: S-EPMC6013495 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

altmetric image

Publications

Development of a Novel Backbone Cyclic Peptide Inhibitor of the Innate Immune TLR/IL1R Signaling Protein MyD88.

Dishon Shira S   Schumacher Adi A   Fanous Joseph J   Talhami Alaa A   Kassis Ibrahim I   Karussis Dimitrios D   Gilon Chaim C   Hoffman Amnon A   Nussbaum Gabriel G  

Scientific reports 20180621 1


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 propert  ...[more]

Similar Datasets

| S-EPMC5484644 | biostudies-literature
| S-EPMC6478521 | biostudies-literature
| S-EPMC7608278 | biostudies-literature
| S-EPMC3697849 | biostudies-literature
| S-EPMC7054668 | biostudies-literature
| S-EPMC7689096 | biostudies-literature
| S-EPMC5344209 | biostudies-literature
| S-EPMC3881181 | biostudies-other
| S-EPMC3931520 | biostudies-literature
| S-EPMC7464415 | biostudies-literature