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 and Harris, Nicholas and Il’kova, Gabriela and Rehák, Pavol and Zsila, Ferenc and Yurgenzon Kogana, Faina and Lahmy, Orly and Zhuk, Regina and Gregor, Paul and Koppel, Juraj (2018) 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 (1). pp. 307-314. ISSN 0360-3997

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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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