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RX-207, a Small Molecule Inhibitor of Protein Interaction with Glycosaminoglycans (SMIGs), Reduces Experimentally Induced Inflammation and Increases Survival Rate in Cecal Ligation and Puncture (CLP)-Induced Sepsis

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Abstract

The fused quinazolinone derivative, RX-207, is chemically and functionally related to small molecule inhibitors of protein binding to glycosaminoglycans (SMIGs). Composed of a planar aromatic amine scaffold, it inhibits protein binding to glycosaminoglycans (GAGs). RX-207 reduced neutrophil migration in thioglycollate-induced peritonitis (37%), inhibited carrageenan-induced paw edema (32%) and cerulein-induced pancreatitis (28%), and increased animal survival in the mouse model of cecal ligation and puncture (CLP)-induced sepsis (60%). The mechanism of RX-207 action, analyzed by UV spectroscopy, confirmed that which was elucidated for chemically related anti-inflammatory SMIGs. RX-207 binding to cell surface GAGs can account for the inhibition of neutrophil recruitment via the micro-vasculature and as a consequence, the reduction of neutrophil mediated tissue damage in the animal models of inflammation and improved survival of mice in CLP-induced sepsis.

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Funding

This study was supported by the Project No. ITMS 26220120066 of the Research and Development Operational Program funded by the European Regional Development Fund.

Author information

Author notes

  1. Stefan Juhas

    Present address: GYN-FIV a.s., Záhradnícka 42, 821 085, Bratislava, Slovakia

  2. Gabriela Il’kova

    Present address: Institute of Animal Physiology and Genetics of the ASCR, v. v. i., Rumburská 89, 277 21, Libechov, Czech Republic

Authors and Affiliations

  1. Institute of Animal Physiology, Slovak Academy of Sciences, 04001, Kosice, Slovakia

    Stefan Juhas, Gabriela Il’kova, Pavol Rehák & Juraj Koppel

  2. Rimonyx Pharmaceuticals Ltd., Rabin Science Park, 70400, Ness-Ziona, Israel

    Nicholas Harris, Faina Yurgenzon Kogan, Orly Lahmy, Regina Zhuk & Paul Gregor

  3. Ephraim Katzir Department of Biotechnology Engineering, ORT Braude Academic College of Engineering, Snonit 51, 2161002, Karmiel, Israel

    Nicholas Harris

  4. Biomolecular Self-Assembly Group, Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary

    Ferenc Zsila

  5. GISMO Therapeutics Inc., A253 ASTECC-UK, Lexington, KY, 40506, USA

    Paul Gregor

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  1. Stefan Juhas
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Correspondence to Nicholas Harris or Paul Gregor.

Ethics declarations

The animal experiments were reviewed and approved by the Ethical Committee for animal experimentation of the Institute of Animal Physiology, approved by the State Veterinary and Food Administration of the Slovak Republic and were performed in accordance with Slovak legislation based on EC Directive 86/609/EEC on the protection of animals used for experimental and other scientific purposes.

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Juhas, S., Harris, N., Il’kova, G. et al. RX-207, a Small Molecule Inhibitor of Protein Interaction with Glycosaminoglycans (SMIGs), Reduces Experimentally Induced Inflammation and Increases Survival Rate in Cecal Ligation and Puncture (CLP)-Induced Sepsis. Inflammation 41, 307–314 (2018). https://doi.org/10.1007/s10753-017-0688-0

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