OBJECTIVE AND DESIGN: Elucidate the mechanism of action of the small molecule inhibitor of protein binding to glycosaminoglycans, RX-111 and assay its anti-inflammatory activity in animal models of inflammatory disease. MATERIALS: The glycosaminoglycan, heparin, was used in the mechanism of action study of RX-111. Human T lymphocytes and umbilical vein endothelial cells were used to assay the in vitro activity of RX-111. Mouse and rat models of disease were used to assay the anti-inflammatory activity of RX-111 in vivo. METHODS: Circular dichroism and UV/Vis absorption spectroscopy were used to study the binding of RX-111 to the glycosaminoglycan, heparin. T lymphocyte rolling on endothelial cells under shear flow was used to assay RX-111 activity in vitro. Delayed-type hypersensitivity (DTH) and tri-nitrobenzene sulfonic acid (TNBS)-induced colitis in mice and experimental autoimmune encephalomyelitis (EAE) in rats were used to assay anti-inflammatory activity of RX-111 in vivo. RESULTS: RX-111 was shown to bind directly to heparin. It inhibited leukocyte rolling on endothelial cells under shear flow and reduced inflammation in the mouse model of DTH. RX-111 was efficacious in the mouse model of inflammatory bowel disease, TNBS-induced colitis and the rat model of multiple sclerosis, EAE. CONCLUSIONS: RX-111 exercises its broad spectrum anti-inflammatory activity by a singular mechanism of action, inhibition of protein binding to the cell surface GAG, heparan sulfate. RX-111 and related thieno[2,3-c]pyridine derivatives are potential therapeutics for the treatment of inflammatory and autoimmune diseases.
- MeSH
- antiflogistika farmakologie terapeutické užití MeSH
- encefalitogenní základní proteiny imunologie MeSH
- encefalomyelitida autoimunitní experimentální farmakoterapie imunologie MeSH
- endoteliální buňky pupečníkové žíly (lidské) účinky léků imunologie MeSH
- heparitinsulfát metabolismus MeSH
- kolitida chemicky indukované farmakoterapie imunologie MeSH
- krysa rodu rattus MeSH
- kyselina trinitrobenzensulfonová MeSH
- lidé MeSH
- myši inbrední BALB C MeSH
- nádorové buněčné linie MeSH
- oxazolon MeSH
- potkani inbrední LEW MeSH
- pozdní přecitlivělost chemicky indukované farmakoterapie imunologie MeSH
- pyridiny farmakologie terapeutické užití MeSH
- rolling leukocytů účinky léků MeSH
- T-lymfocyty účinky léků imunologie MeSH
- thiofeny farmakologie terapeutické užití MeSH
- výsledek terapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
