Inflammation Research

, Volume 65, Issue 4, pp 285–294 | Cite as

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

  • Nicholas HarrisEmail author
  • Juraj Koppel
  • Ferenc Zsila
  • Stefan Juhas
  • Gabriela Il’kova
  • Faina Yurgenzon Kogan
  • Orly Lahmy
  • Gizi Wildbaum
  • Nathan Karin
  • Regina Zhuk
  • Paul GregorEmail author
Original Research Paper


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.


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.


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.


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.


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.


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



Circular dichroism




Small molecule inhibitors of protein interaction with glycosaminoglycans


High endothelium venules


Heparan sulfate


Human umbilical vein endothelial


Delayed-type hypersensitivity


Experimental autoimmune encephalomyelitis


Myelin basic protein


Myelin oligodendrocyte glycoprotein


Multiple sclerosis


Mucosal addressin cell adhesion molecule 1


Peripheral node addressins


Progressive multifocal leukoencephalopathy



The research was supported by grants (37373, 39243) awarded by the Office of The Chief Scientist, Israel. We are grateful to Mr. Ra’anan Margalit and the late Dr. Valentin Grabovsky for technical assistance and professional advice.

Supplementary material

11_2016_915_MOESM1_ESM.docx (63 kb)
Supplementary material 1 (DOCX 63 kb)

Supplementary material 2 (AVI 1995 kb)

Supplementary material 3 (AVI 2085 kb)


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Copyright information

© Springer International Publishing 2016

Authors and Affiliations

  • Nicholas Harris
    • 1
    • 2
    Email author
  • Juraj Koppel
    • 3
  • Ferenc Zsila
    • 4
  • Stefan Juhas
    • 3
    • 8
  • Gabriela Il’kova
    • 3
    • 7
  • Faina Yurgenzon Kogan
    • 1
  • Orly Lahmy
    • 1
  • Gizi Wildbaum
    • 5
  • Nathan Karin
    • 5
  • Regina Zhuk
    • 1
  • Paul Gregor
    • 1
    • 6
    Email author
  1. 1.Rimonyx Pharmaceuticals Ltd.Ness-ZionaIsrael
  2. 2.Ephraim Katzir Department of Biotechnology EngineeringORT Braude Academic College of EngineeringKarmielIsrael
  3. 3.Institute of Animal PhysiologySlovak Academy of SciencesKosiceSlovakia
  4. 4.Biomolecular Self-Assembly Group, Institute of Materials and Environmental ChemistryResearch Centre for Natural SciencesBudapestHungary
  5. 5.Department of Immunology, Rappaport Institute, Rappaport Faculty of MedicineTechnionHaifaIsrael
  6. 6.GISMO Therapeutics Inc.LexingtonUSA
  7. 7.GYN-FIV a.s.BratislavaSlovakia
  8. 8.Institute of Animal Physiology and Genetics of the ASCR, v. v. i.LiběchovCzech Republic

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