Small Molecule Analogues of the parasitic worm product ES-62 interact with the TIR domain of MyD88 to inhibit pro-inflammatory signalling

Suckling, Colin J.; Alam, Shahabuddin; Olson, Mark A.; Saikh, Kamal U.; Harnett, Margaret M.; Harnett, William

doi:10.1038/s41598-018-20388-z

Cited by 22 publications

(20 citation statements)

References 44 publications

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“…Fig. S3G shows that co-immunoprecipitation (co-IP) samples from cells treated with IL-1β produced stronger bands than from cells not untreated samples, as shown by others 64 . Cells were lysed in Ripa buffer in the presence of protease inhibitors and incubated on ice for 25 min.…”

Section: Methodssupporting

confidence: 74%

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

Dishon

Schumacher

Fanous

et al. 2018

Sci Rep

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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.

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Section: Methodssupporting

confidence: 74%

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

Dishon

Schumacher

Fanous

et al. 2018

Sci Rep

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show abstract

“…Our examinations to date indicate that active SMAs like 11a and 12b mimic a primary ES-62 mechanism of action in causing autophagolysosomal degradation of the TLR/IL-1R adaptor molecule MyD88 (Al-Riyami et al, 2013;Rzepecka et al, 2015b;Rodgers et al 2015). Indeed, recently we have found that this reflects direct interaction between the SMAs and the TIR domain of MyD88 (Suckling et al 2018).…”

Section: Introductionmentioning

confidence: 70%

Synthetic analogues of the parasitic worm product ES-62 reduce disease development in in vivo models of lung fibrosis

et al. 2018

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Parasitic worms are receiving much attention as a potential new therapeutic approach to treating autoimmune and allergic conditions but concerns remain regarding their safety. As an alternative strategy, we have focused on the use of defined parasitic worm products and recently taken this one step further by designing drug-like small molecule analogues of one such product, ES-62, which is anti-inflammatory by virtue of covalently attached phosphorylcholine moieties. Previously, we have shown that ES-62 mimics are efficacious in protecting against disease in mouse models of rheumatoid arthritis, systemic lupus erythematosus and skin and lung allergy. Given the potential role of chronic inflammation in fibrosis, in the present study we have focused our attention on lung fibrosis, a debilitating condition for which there is no cure and which in spite of treatment slowly gets worse over time. Two mouse models of fibrosis - bleomycin-induced and LPS-induced - in which roles for inflammation have been implicated were adopted. Four ES-62 analogues were tested - 11a and 12b, previously shown to be active in mouse models of allergic and autoimmune disease and 16b and AIK-29/62 both of which are structurally related to 11a. All four compounds were found to significantly reduce disease development in both fibrosis models, as shown by histopathological analysis of lung tissue, indicating their potential as treatments for this condition.

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“…Finally, it has recently become apparent that the primary effect of ES-62 and the SMAs on immune system cells is to down-regulate the aberrantly elevated MyD88-dependent responses pertaining during chronic inflammation, restoring them back towards the steady-state levels observed in healthy animals. This has been observed with macrophages [ 6 ], dendritic cells [ 51 ], mast cells [ 52 ], and Th17 cells [ 30 ], and at least in the case of the SMAs, has been shown to reflect direct interaction with the MyD88 TIR domain [ 53 ]. Interestingly, mice lacking MyD88 are resistant to the development of EAE [ 54 ] and this may suggest that ES-62/SMAs’ mechanism of action involving reduction rather than the abrogation of adaptor levels [ 6 , 30 , 51 , 52 ] may be insufficient to achieve protection against inflammatory responses in this particular model.…”

Section: Discussionmentioning

confidence: 97%

Failure of the Anti-Inflammatory Parasitic Worm Product ES-62 to Provide Protection in Mouse Models of Type I Diabetes, Multiple Sclerosis, and Inflammatory Bowel Disease

et al. 2018

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Parasitic helminths and their isolated secreted products show promise as novel treatments for allergic and autoimmune conditions in humans. Foremost amongst the secreted products is ES-62, a glycoprotein derived from Acanthocheilonema viteae, a filarial nematode parasite of gerbils, which is anti-inflammatory by virtue of covalently-attached phosphorylcholine (PC) moieties. ES-62 has been found to protect against disease in mouse models of rheumatoid arthritis, systemic lupus erythematosus, and airway hyper-responsiveness. Furthermore, novel PC-based synthetic small molecule analogues (SMAs) of ES-62 have recently been demonstrated to show similar anti-inflammatory properties to the parent molecule. In spite of these successes, we now show that ES-62 and its SMAs are unable to provide protection in mouse models of certain autoimmune conditions where other helminth species or their secreted products can prevent disease development, namely type I diabetes, multiple sclerosis and inflammatory bowel disease. We speculate on the reasons underlying ES-62’s failures in these conditions and how the negative data generated may help us to further understand ES-62’s mechanism of action.

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Small Molecule Analogues of the parasitic worm product ES-62 interact with the TIR domain of MyD88 to inhibit pro-inflammatory signalling

Cited by 22 publications

References 44 publications

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

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

Synthetic analogues of the parasitic worm product ES-62 reduce disease development in in vivo models of lung fibrosis

Failure of the Anti-Inflammatory Parasitic Worm Product ES-62 to Provide Protection in Mouse Models of Type I Diabetes, Multiple Sclerosis, and Inflammatory Bowel Disease

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