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

Authors
  • Kalluri, Mani D
  • Datla, Praneel
  • Bellary, Akshaya
  • Basha, Khalander
  • Sharma, Ashwani
  • Sharma, Anuradha
  • Singh, Shiva
  • Upadhyay, Shakti
  • Rajagopal, Vikram
Type
Published Article
Journal
FEBS Journal
Publisher
Wiley (Blackwell Publishing)
Publication Date
Apr 01, 2010
Volume
277
Issue
7
Pages
1639–1652
Identifiers
DOI: 10.1111/j.1742-4658.2010.07589.x
PMID: 20180845
Source
Medline
License
Unknown

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.

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