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 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.

Oral aktive Peptide: Gibt es ein Patentrezept?

“…[188] Es wurde für c(MyD 4-4) berichtet, dass es die Dimerisierung von MyD88 stçrt und die Makrophagen-TLR2-und TLR4-Stimulierung von Mensch und Maus blockiert. [188] Es wurde für c(MyD 4-4) berichtet, dass es die Dimerisierung von MyD88 stçrt und die Makrophagen-TLR2-und TLR4-Stimulierung von Mensch und Maus blockiert.…”

Orally Active Peptides: Is There a Magic Bullet?

“…This bioactive ligand enhances VEGF-mediated angiogenic sprouting and thus could be used in combination with chemotherapeutics to treat cancer. [188] c(MyD 4-4) was reported to disrupt the dimerization of MyD88 and to block human and mouse macrophage TLR2 and TLR4 stimulation. MyR-c (MyD 4-4) Inhibition of MyD88, ac ytoplasmic adopter protein, by the recently developed cyclic peptide c(MyD 4-4) was shown to be beneficial for treating autoimmune diseases.…”

“…Inhibition of MyD88, a cytoplasmic adopter protein, by the recently developed cyclic peptide c (MyD 4‐4) was shown to be beneficial for treating autoimmune diseases . c (MyD 4‐4) was reported to disrupt the dimerization of MyD88 and to block human and mouse macrophage TLR2 and TLR4 stimulation.…”

Quantitative proteomic analysis after neuroprotective MyD88 inhibition in the retinal degeneration 10 mouse

“…Therefore, MyD88 has been considered as a potential target to block aberrant activation of TLR during neurodegeneration. 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 …”

“…Therefore, MyD88 has been considered as a potential target to block aberrant activation of TLR during neurodegeneration. [5][6][7][8][9][10][11][12][13] We recently demonstrated that inhibiting MyD88 by gene knockout 14 and pharmacologic inhibitor 2 led to higher photoreceptor survival in two mouse models of retinal degeneration. Furthermore, neuroprotection from inhibiting MyD88 in the rd10 mouse model of retinal degeneration was associated with increased microglia/macrophage expressing the Arg1 neuroprotective marker and altered levels of several anti-inflammatory cytokines.…”