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Plos Biology : Identification of Human S100A9 as a Novel Target for Treatment of Autoimmune Disease Via Binding to Quinoline-3-carboxamides, Volume 7

By Akira, Shizuo

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Book Id: WPLBN0003930786
Format Type: PDF eBook :
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Reproduction Date: 2015

Title: Plos Biology : Identification of Human S100A9 as a Novel Target for Treatment of Autoimmune Disease Via Binding to Quinoline-3-carboxamides, Volume 7  
Author: Akira, Shizuo
Volume: Volume 7
Language: English
Subject: Journals, Science, Biology
Collections: Periodicals: Journal and Magazine Collection (Contemporary), PLoS Biology
Publication Date:
Publisher: Plos

Description : Despite more than 25 years of research, the molecular targets of quinoline-3-carboxamides have been elusive although these compounds are currently in Phase II and III development for treatment of autoimmune/inflammatory diseases in humans. Using photoaffinity cross-linking of a radioactively labelled quinoline-3-carboxamide compound, we could determine a direct association between human S100A9 and quinoline-3-carboxamides. This interaction was strictly dependent on both Znþþ and Caþþ. We also show that S100A9 in the presence of Znþþ and Caþþ is an efficient ligand of receptor for advanced glycation end products (RAGE) and also an endogenous Toll ligand in that it shows a highly specific interaction with TLR4/MD2. Both these interactions are inhibited by quinoline-3-carboxamides. A clear structure-activity relationship (SAR) emerged with regard to the binding of quinoline-3-carboxamides to S100A9, as well as these compounds potency to inhibit interactions with RAGE or TLR4/MD2. The same SAR was observed when the compound’s ability to inhibit acute experimental autoimmune encephalomyelitis in mice in vivo was analysed. Quinoline-3-carboxamides would also inhibit TNFa release in a S100A9-dependent model in vivo, as would antibodies raised against the quinoline-3-carboxamide–binding domain of S100A9. Thus, S100A9 appears to be a focal molecule in the control of autoimmune disease via its interactions with proinflammatory mediators. The specific binding of quinoline-3-carboxamides to S100A9 explains the immunomodulatory activity of this class of compounds and defines S100A9 as a novel target for treatment of human autoimmune diseases.


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