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

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.

• Authors: D T Rodgers, M A Pineda, C J Suckling, W Harnett, M M Harnett
• Journal: Lupus (Lupus) Vol. 24 Issue 13 Pg. 1437-42 (Nov 2015) ISSN: 1477-0962 [Electronic] England
• PMID: 26085597 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2015.

Chemical References

• Adjuvants, Immunologic
• Antibodies, Antinuclear
• Cytokines
• ES-62 protein, Acanthocheilonema viteae
• Helminth Proteins
• Immunologic Factors
• Interleukin-6
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88

Topics

• Adjuvants, Immunologic (pharmacology)
• Animals
• Antibodies, Antinuclear (metabolism)
• Cytokines (metabolism)
• Disease Models, Animal
• Female
• Helminth Proteins (pharmacology)
• Immunologic Factors
• Interleukin-6 (metabolism)
• Lupus Erythematosus, Systemic (drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred MRL lpr
• Myeloid Differentiation Factor 88 (genetics)
• Nephritis (drug therapy, pathology)
• Proteinuria (drug therapy, pathology)