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
Language English Country Switzerland Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
26794621
DOI
10.1007/s00011-016-0915-4
PII: 10.1007/s00011-016-0915-4
Knihovny.cz E-resources
- Keywords
- Autoimmune disease, Glycosaminoglycan, Heparan sulfate, Heparin binding protein, Inflammation, Small molecule drug,
- MeSH
- Anti-Inflammatory Agents pharmacology therapeutic use MeSH
- Myelin Basic Protein immunology MeSH
- Encephalomyelitis, Autoimmune, Experimental drug therapy immunology MeSH
- Human Umbilical Vein Endothelial Cells drug effects immunology MeSH
- Heparitin Sulfate metabolism MeSH
- Colitis chemically induced drug therapy immunology MeSH
- Rats MeSH
- Trinitrobenzenesulfonic Acid MeSH
- Humans MeSH
- Mice, Inbred BALB C MeSH
- Cell Line, Tumor MeSH
- Oxazolone MeSH
- Rats, Inbred Lew MeSH
- Hypersensitivity, Delayed chemically induced drug therapy immunology MeSH
- Pyridines pharmacology therapeutic use MeSH
- Leukocyte Rolling drug effects MeSH
- T-Lymphocytes drug effects immunology MeSH
- Thiophenes pharmacology therapeutic use MeSH
- Treatment Outcome MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Anti-Inflammatory Agents MeSH
- Myelin Basic Protein MeSH
- Heparitin Sulfate MeSH
- Trinitrobenzenesulfonic Acid MeSH
- Oxazolone MeSH
- Pyridines MeSH
- RX-111 MeSH Browser
- Thiophenes 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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