Mechanism of action and efficacy of RX-111, a thieno[2,3-c]pyridine derivative and small molecule inhibitor of protein interaction with glycosaminoglycans (SMIGs), in delayed-type hypersensitivity, TNBS-induced colitis and experimental autoimmune encephalomyelitis
Jazyk angličtina Země Švýcarsko Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
26794621
DOI
10.1007/s00011-016-0915-4
PII: 10.1007/s00011-016-0915-4
Knihovny.cz E-zdroje
- Klíčová slova
- Autoimmune disease, Glycosaminoglycan, Heparan sulfate, Heparin binding protein, Inflammation, Small molecule drug,
- 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
- Názvy látek
- antiflogistika MeSH
- encefalitogenní základní proteiny MeSH
- heparitinsulfát MeSH
- kyselina trinitrobenzensulfonová MeSH
- oxazolon MeSH
- pyridiny MeSH
- RX-111 MeSH Prohlížeč
- thiofeny MeSH
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.
Department of Immunology Rappaport Institute Rappaport Faculty of Medicine Technion Haifa Israel
GISMO Therapeutics Inc A253 ASTECC UK Lexington KY 40506 USA
GYN FIV a s Záhradnícka 42 821 085 Bratislava Slovakia
Institute of Animal Physiology Slovak Academy of Sciences 04001 Kosice Slovakia
Rimonyx Pharmaceuticals Ltd Rabin Science Park 70400 Ness Ziona Israel
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