title: Drug-like analogues of the parasitic worm-derived immunomodulator ES-62 are therapeutic in the MRL/Lpr model of systemic lupus erythematosus.
abstract: BACKGROUND
  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.affiliation: Institute of Infection, Immunity and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, UK.
authors.forename: D T
authors.initials: DT
authors.lastname: Rodgers
authors.affiliation: Institute of Infection, Immunity and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, UK.
authors.forename: M A
authors.initials: MA
authors.lastname: Pineda
authors.affiliation: Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow, UK.
authors.forename: C J
authors.initials: CJ
authors.lastname: Suckling
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.
authors.forename: W
authors.initials: W
authors.lastname: Harnett
authors.affiliation: 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.
authors.forename: M M
authors.initials: MM
authors.lastname: Harnett
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000974:Antibodies, Antinuclear / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015801:Helminth Proteins / Q000494:pharmacology*; D007155:Immunologic Factors; D015850:Interleukin-6 / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D009393:Nephritis / Q000188:drug therapy / Q000473:pathology; D011507:Proteinuria / Q000188:drug therapy / Q000473:pathology
chemical_list: D000276:Adjuvants, Immunologic; D000974:Antibodies, Antinuclear; D016207:Cytokines; C435884:ES-62 protein, Acanthocheilonema viteae; D015801:Helminth Proteins; D007155:Immunologic Factors; D015850:Interleukin-6; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88
keywords: ES-62; MRL/Lpr mouse; MyD88; SLE; antinuclear antibody (ANA); inflammation; nephritis; parasitic helminth