RX-207, a Small Molecule Inhibitor of Protein Interaction with Glycosaminoglycans (SMIGs), Reduces Experimentally Induce
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ORIGINAL ARTICLE
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 Stefan Juhas,1,2 Nicholas Harris,3,4,8 Gabriela Il’kova,1,5 Pavol Rehák,1 Ferenc Zsila,6 Faina Yurgenzon Kogan,3 Orly Lahmy,3 Regina Zhuk,3 Paul Gregor,3,7,8 and Juraj Koppel1
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. KEY WORDS: heparin binding protein; glycosaminoglycan; neutrophil; inflammation; sepsis.
1
Institute of Animal Physiology, Slovak Academy of Sciences, 04001 Kosice, Slovakia 2 GYN-FIV a.s., Záhradnícka 42, 821 085 Bratislava, Slovakia 3 Rimonyx Pharmaceuticals Ltd., Rabin Science Park, 70400 Ness-Ziona, Israel 4 Ephraim Katzir Department of Biotechnology Engineering, ORT Braude Academic College of Engineering, Snonit 51, 2161002 Karmiel, Israel 5 Institute of Animal Physiology and Genetics of the ASCR, v. v. i., Rumburská 89, 277 21 Libechov, Czech Republic 6 Biomolecular Self-Assembly Group, Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary 7 GISMO Therapeutics Inc., A253 ASTECC-UK, Lexington, KY 40506, USA 8 To whom correspondence should be addressed to Nicholas Harris at Ephraim Katzir Department of Biotechnology Engineering, ORT Braude Academic College of Engineering, Snonit 51, 2161002 Karmiel, Israel. E-mail: [email protected]; and Paul Gregor at GISMO Therapeutics Inc., A253 ASTECC-UK, Lexington, KY 40506, USA. E-mail: [email protected]
INTRODUCTION Contemporary medicine treats inflammatory disorders with a variety of medications. Corticosteroids are the most effective drugs for acute inflammation and are efficacious, at a low dose, in treating chronic inflammation [1]. Inflammatory disorders that are refractory to treatment, such as acute pancreatitis and sepsis, can be fatal. The absence of effective treatment of sepsis is not for want of effort, or resource. There are more than 400 reports of preclinical studies of the pro-inflammatory cytok
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