Novel synthetic gluco-disaccharide RSCL-0409--a lipopolysaccharide-induced Toll-like receptor-mediated signalling antagonist

FEBS J. 2010 Apr;277(7):1639-52. doi: 10.1111/j.1742-4658.2010.07589.x. Epub 2010 Feb 17.

Abstract

The regulation of cytokines and pro-inflammatory genes is an absolute essentiality to combat inflammatory diseases. The present study investigated the effects of 4-O-chloroacetyl-2,3-di-O-acetyl-6-O-levulinoyl-beta-d-glucopyranosyl]-(1-3)-1-O-(p-methoxyphenyl)-2-deoxy-2-N-trichloroacetyl-4,6-O-benzylidene-alpha-d-glucopyranoside (RSCL-0409), a novel small molecule Toll-like receptor (TLR) signalling antagonist, and its mechanism of action in human monocytic (THP-1) cells stimulated with lipopolysaccharide (LPS). In THP-1 and RAW264.7 cells, RSCL-0409 suppressed LPS-induced production of tumour necrosis factor-alpha (TNF-alpha) with a 50% inhibitory concentration of 10.6 mum and mRNA expression of ICAM-1, Cox-2 and interleukin-8 with no evidence of cytotoxicity. RSCL-0409 also suppressed TNF-alpha production from LPS-stimulated human peripheral blood mononuclear cells. Similar results were obtained in vivo in a murine model of LPS-induced inflammation, where pretreatment with RSCL-0409 resulted in significant inhibition of TNF-alpha. It is also noteworthy that RSCL-0409 suppressed the cytokine production induced by TLR2 and -4 ligands and not for any other TLR ligands. RSCL-0409 significantly inhibited p65 nuclear translocation induced by LPS. In conclusion, RSCL-0409, a novel small molecule, is the first of its kind in the category of carbohydrate-derived TLR signalling antagonists and could definitely be a promising therapeutic agent for inflammatory diseases whose pathogenesis involves TLR2- or TLR4-mediated signalling processes.

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Disaccharides / chemistry*
  • Disaccharides / pharmacology
  • Female
  • Humans
  • Inflammation
  • Leukocytes, Mononuclear / cytology
  • Ligands
  • Lipopolysaccharides / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Models, Biological
  • NF-kappa B / metabolism
  • Signal Transduction
  • Toll-Like Receptors / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • 4-O-chloroacetyl-2,3-di-O-acetyl-6-O-levulinoylglucopyranosyl-(1-3)-1-O-(p-methoxyphenyl)-2-deoxy-2-N-trichloroacetyl-4,6-O-benzylideneglucopyranoside
  • Disaccharides
  • Ligands
  • Lipopolysaccharides
  • NF-kappa B
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha