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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

Juhas, Stefan
Author Juhas, Stefan Institute of Animal Physiology, Slovak Academy of Sciences, 04001, Kosice, Slovakia GYN-FIV a.s., Záhradnícka 42, 821 085, Bratislava, Slovakia
Harris, Nicholas
Author Harris, Nicholas Rimonyx Pharmaceuticals Ltd., Rabin Science Park, 70400, Ness-Ziona, Israel. nharris@braude.ac.il Ephraim Katzir Department of Biotechnology Engineering, ORT Braude Academic College of Engineering, Snonit 51, 2161002, Karmiel, Israel. nharris@braude.ac.il
Il'kova, Gabriela
Author Il'kova, Gabriela Institute of Animal Physiology, Slovak Academy of Sciences, 04001, Kosice, Slovakia Institute of Animal Physiology and Genetics of the ASCR, v. v. i., Rumburská 89, 277 21, Libechov, Czech Republic
Rehák, Pavol
Author Rehák, Pavol Institute of Animal Physiology, Slovak Academy of Sciences, 04001, Kosice, Slovakia
Zsila, Ferenc
Author Zsila, Ferenc Biomolecular Self-Assembly Group, Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
Yurgenzon Kogan, Faina
Author Yurgenzon Kogan, Faina Rimonyx Pharmaceuticals Ltd., Rabin Science Park, 70400, Ness-Ziona, Israel
Lahmy, Orly
Author Lahmy, Orly Rimonyx Pharmaceuticals Ltd., Rabin Science Park, 70400, Ness-Ziona, Israel
Zhuk, Regina
Author Zhuk, Regina Rimonyx Pharmaceuticals Ltd., Rabin Science Park, 70400, Ness-Ziona, Israel
Gregor, Paul
Author Gregor, Paul Rimonyx Pharmaceuticals Ltd., Rabin Science Park, 70400, Ness-Ziona, Israel. paul@gismotherapeutics.com GISMO Therapeutics Inc., A253 ASTECC-UK, Lexington, KY, 40506, USA. paul@gismotherapeutics.com
Koppel, Juraj
Author Koppel, Juraj Institute of Animal Physiology, Slovak Academy of Sciences, 04001, Kosice, Slovakia

Inflammation. 2018 Feb ; 41 (1) : 307-314.

ISSN 1573-2576 | 0360-3997
Source

Language English Country United States Media print

Document type Journal Article

Persistent link https://www.medvik.cz/link/pmid29110154

Grant support
ITMS 26220120066 ERDF

PubMed 29110154
DOI 10.1007/s10753-017-0688-0
PII: 10.1007/s10753-017-0688-0
Knihovny.cz E-resources

Keywords
glycosaminoglycan, heparin binding protein, inflammation, neutrophil, sepsis,
MeSH
Anti-Inflammatory Agents pharmacology MeSH
Cell Adhesion drug effects MeSH
Cecum microbiology surgery MeSH
Quinazolinones pharmacology MeSH
Edema chemically induced metabolism pathology prevention & control MeSH
Glycosaminoglycans metabolism MeSH
Neutrophil Infiltration drug effects MeSH
Ligation MeSH
Disease Models, Animal MeSH
Mice, Inbred BALB C MeSH
Neutrophils drug effects metabolism microbiology MeSH
Pancreatitis chemically induced metabolism pathology prevention & control MeSH
Peritonitis chemically induced metabolism pathology prevention & control MeSH
Punctures MeSH
Sepsis metabolism microbiology pathology prevention & control MeSH
Protein Binding MeSH
Animals MeSH
Check Tag
Animals MeSH
Publication type
Journal Article MeSH
Names of Substances
Anti-Inflammatory Agents MeSH
Quinazolinones MeSH
Glycosaminoglycans MeSH

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.

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

Ephraim Katzir Department of Biotechnology Engineering ORT Braude Academic College of Engineering Snonit 51 2161002 Karmiel 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 and Genetics of the ASCR v v i Rumburská 89 277 21 Libechov Czech Republic

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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