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Inflamm Res. 2016 Apr;65(4):285-94. doi: 10.1007/s00011-016-0915-4. Epub 2016 Jan 21.

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.

Author information

1
Rimonyx Pharmaceuticals Ltd., Rabin Science Park, 70400, Ness-Ziona, Israel. nharris@braude.ac.il.
2
Ephraim Katzir Department of Biotechnology Engineering, ORT Braude Academic College of Engineering, 21982, Karmiel, Israel. nharris@braude.ac.il.
3
Institute of Animal Physiology, Slovak Academy of Sciences, 04001, Kosice, Slovakia.
4
Biomolecular Self-Assembly Group, Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Budapest, Hungary.
5
Institute of Animal Physiology and Genetics of the ASCR, v. v. i., Rumburská 89, 277 21, Liběchov, Czech Republic.
6
GYN-FIV a.s., Záhradnícka 42, 821 085, Bratislava, Slovakia.
7
Rimonyx Pharmaceuticals Ltd., Rabin Science Park, 70400, Ness-Ziona, Israel.
8
Department of Immunology, Rappaport Institute, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
9
Rimonyx Pharmaceuticals Ltd., Rabin Science Park, 70400, Ness-Ziona, Israel. paul@gismotherapeutics.com.
10
GISMO Therapeutics Inc., A253 ASTECC-UK, Lexington, KY, 40506, USA. paul@gismotherapeutics.com.

Abstract

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.

KEYWORDS:

Autoimmune disease; Glycosaminoglycan; Heparan sulfate; Heparin binding protein; Inflammation; Small molecule drug

PMID:
26794621
DOI:
10.1007/s00011-016-0915-4
[Indexed for MEDLINE]

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