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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Lupus Erythematosus, Systemic / metabolism
  • Lupus Erythematosus, Systemic / pathology
  • Mice
  • Mice, Inbred MRL lpr*
  • Myeloid Differentiation Factor 88 / genetics
  • Nephritis / drug therapy
  • Nephritis / pathology
  • Proteinuria / drug therapy
  • Proteinuria / pathology

Substances

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