Novel synthetic gluco-disaccharide RSCL-0409--a lipopolysaccharide-induced Toll-like receptor-mediated signalling antagonist.
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.
Kalluri
Mani D
MD
Drug Discovery and Development Group, Reliance Life Sciences Pvt. Ltd, Navi Mumbai, India.
Datla
Praneel
P
Bellary
Akshaya
A
Basha
Khalander
K
Sharma
Ashwani
A
Sharma
Anuradha
A
Singh
Shiva
S
Upadhyay
Shakti
S
Rajagopal
Vikram
V
D021581:Active Transport, Cell Nucleus; D000818:Animals; D004187:Disaccharides / Q000737:chemistry* / Q000494:pharmacology; D005260:Female; D006801:Humans; D007249:Inflammation; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008024:Ligands; D008070:Lipopolysaccharides / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C549036:4-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; D004187:Disaccharides; D008024:Ligands; D008070:Lipopolysaccharides; D016328:NF-kappa B; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha