Drug-like analogues of the parasitic worm-derived immunomodulator ES-62 are therapeutic in the MRL/Lpr model of systemic lupus erythematosus. (November 2015)

• Record Type: Journal Article
• Authors: Rodgers, D T; Pineda, M A; Suckling, C J; Harnett, W; Harnett, M M
• Is Part Of: Lupus. Volume 24:Number 13(2015)
• Page Start: 1437
• Page End: 1442
• Publication Date: 2015-11
• Subjects: SLE -- MRL/Lpr mouse -- inflammation -- antinuclear antibody (ANA) -- nephritis -- parasitic helminth -- ES-62 -- MyD88; Systemic lupus erythematosus -- Periodicals; 616.772005
• DOI: 10.1177/0961203315591031
• Languages: English
• ISSNs: 0961-2033

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.