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.
Highlights
ES-62, a secreted product of the parasitic filarial nematode, Acanthocheilonema viteae[1], has been shown in a number of studies to be a highly effective immunomodulatory agent
There may be additional targets for the Small Molecule Analogues (SMAs), it is likely that the primary target, as with ES-62, is MyD884,10,20, a 31–33 kDa adaptor protein consisting of a so-called N-terminal death domain and a C-terminal Toll/interleukin-1 receptor (TLR/IL-1R; TIR) domain separated by a short linker region, which acts as an anchor, recruiting signal transducers to TLRs/IL-1R and other receptors including that for IFN-γ21–26
Because T5910047 was derived from in silico screening of roughly 5 million compounds without ligand-binding optimization or refinement and showed an inhibition level as a minimal threshold for compound selection, the T5910047 score is used as a benchmark for assessing the three ES-62 SMA compounds
Summary
ES-62, a secreted product of the parasitic filarial nematode, Acanthocheilonema viteae[1], has been shown in a number of studies to be a highly effective immunomodulatory agent This molecule can interfere with the pro-inflammatory responses of various immune system cells including B cells, dendritic cells (DCs), macrophages and mast cells. Compound T6167923 was found to have therapeutic efficacy in protecting mice from staphylococcal enterotoxin B (SEB)-induced septic shock following administration of a single dose[33] The similarity of these T-series compounds in terms of immunological profile (reducing the release of pro-inflammatory cytokines from stimulated cells) with that of the SMAs of ES-62 together with a number of common structural features with the SMA library suggested that it was possible that the active SMAs, 11a and 12b, by binding to the same or nearby sites on the MyD88 surface, might disrupt its dimerisation. Their effects on MyD88 protein complex formation and its downstream consequences were evaluated
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