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Identification of human S100A9 as a novel target for treatment of autoimmune disease via binding to quinoline-3-carboxamides.

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Author

  • Per Björk
  • Anders Björk
  • Thomas Vogl
  • Martin Stenström
  • David Liberg
  • Anders Olsson
  • Johannes Roth
  • Fredrik Ivars
  • Tomas Leanderson

Summary, in English

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 Zn++ and Ca++. We also show that S100A9 in the presence of Zn++ and Ca++ 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 TNFalpha 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.

Department/s

  • Immunology

Publishing year

2009

Language

English

Pages

800-812

Publication/Series

PLoS Biology

Volume

7

Issue

4

Document type

Journal article

Publisher

Public Library of Science (PLoS)

Topic

  • Biological Sciences

Status

Published

Research group

  • Immunology

ISBN/ISSN/Other

  • ISSN: 1545-7885