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

Suckling, C. J., Alam, S., Olson, M. A., Saikh, K. U., Harnett, M. M. and Harnett, W. (2018) Small Molecule Analogues of the parasitic worm product ES-62 interact with the TIR domain of MyD88 to inhibit pro-inflammatory signalling. Scientific Reports, 8(1), 2123. (doi:10.1038/s41598-018-20388-z) (PMID:29391452) (PMCID:PMC5794923)

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Abstract

ES-62 is a protein secreted by the parasitic worm Acanthocheilonema viteae that is anti-inflammatory by virtue of covalently attached phosphorylcholine. Previously we have reported that drug-like Small Molecule Analogues (SMAs) of its phosphorylcholine moiety can mimic ES-62 in protecting against disease development in certain mouse models of autoimmune and allergic conditions, due to them causing partial degradation of the TLR/IL-1R adaptor MyD88. We have now taken a molecular modelling approach to investigating the mechanism underlying this effect and this predicts that the SMAs interact directly with the MyD88 TIR domain. Further support for this is provided by assay of LPS-induced MyD88/NF-κB-driven secreted alkaline phosphatase (SEAP) reporter activity in commercially-available stably transfected (TLR4-MD2-NF-κB-SEAP) HEK293 cells, as SMA12b-mediated inhibition of such SEAP activity is blocked by its pre-incubation with recombinant MyD88-TIR domain. Direct binding of SMA12b to the TIR domain is also shown to inhibit homo-dimerization of the adaptor, an event that can explain the observed degradation of the adaptor and inhibition of subsequent downstream signalling. Thus, these new data identify initial events by which drug-like ES-62 SMAs, which we also demonstrate are able to inhibit cytokine production by human cells, homeostatically maintain "safe" levels of MyD88 signalling.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Harnett, Professor Margaret and Harnett, Professor William
Authors: Suckling, C. J., Alam, S., Olson, M. A., Saikh, K. U., Harnett, M. M., and Harnett, W.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Scientific Reports
Publisher:Nature Publishing Group
ISSN:2045-2322
ISSN (Online):2045-2322
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Scientific Reports 8(1):2123
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
455802Small molecule analogues (SMAs) of an immunomodulatory helminth product provide a novel approach to dissecting macrophage signalsMargaret HarnettBiotechnology and Biological Sciences Research Council (BBSRC)BB/E013929/1III -IMMUNOLOGY
495342ES-62, TLR4, the Mast Cell and development of novel drugs for mast cell-mediated inflammationMargaret HarnettWellcome Trust (WELLCOTR)086852/Z/08/ZIII -IMMUNOLOGY