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Lupus. 2015 Nov;24(13):1437-42. doi: 10.1177/0961203315591031. Epub 2015 Jun 17.

Drug-like analogues of the parasitic worm-derived immunomodulator ES-62 are therapeutic in the MRL/Lpr model of systemic lupus erythematosus.

Author information

1
Institute of Infection, Immunity and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, UK.
2
Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow, UK.
3
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.
4
Institute of Infection, Immunity and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, UK Margaret.Harnett@glasgow.ac.uk W.Harnett@strath.ac.uk.

Abstract

INTRODUCTION:

ES-62, a phosphorylcholine (PC)-containing immunomodulator secreted by the parasitic worm Acanthocheilonema viteae, protects against nephritis in the MRL/Lpr mouse model of systemic lupus erythematosus (SLE). However, ES-62 is not suitable for development as a therapy and thus we have designed drug-like small molecule analogues (SMAs) based around its active PC-moiety. To provide proof of concept that ES-62-based SMAs exhibit therapeutic potential in SLE, we have investigated the capacity of two SMAs to protect against nephritis when administered to MRL/Lpr mice after onset of kidney damage.

METHODS:

SMAs 11a and 12b were evaluated for their ability to suppress antinuclear antibody (ANA) generation and consequent kidney pathology in MRL/Lpr mice when administered after the onset of proteinuria.

RESULTS:

SMAs 11a and 12b suppressed development of ANA and proteinuria. Protection reflected downregulation of MyD88 expression by kidney cells and this was associated with reduced production of IL-6, a cytokine that exhibits promise as a therapeutic target for this condition.

CONCLUSIONS:

SMAs 11a and 12b provide proof of principle that synthetic compounds based on the safe immunomodulatory mechanisms of parasitic worms can exhibit therapeutic potential as a novel class of drugs for SLE, a disease for which current therapies remain inadequate.

KEYWORDS:

ES-62; MRL/Lpr mouse; MyD88; SLE; antinuclear antibody (ANA); inflammation; nephritis; parasitic helminth

PMID:
26085597
PMCID:
PMC4616909
DOI:
10.1177/0961203315591031
[Indexed for MEDLINE]
Free PMC Article

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