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

Björk, Per; Björk, Anders; Vogl, Thomas; Stenström, Martin; Liberg, David; Olsson, Anders; Roth, Johannes; Ivars, Fredrik LU and Leanderson, Tomas LU (2009) In PLoS Biology 7(4). p.800-812
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS Biology
volume
7
issue
4
pages
800 - 812
publisher
Public Library of Science
external identifiers
  • wos:000266500000009
  • pmid:19402754
  • scopus:65949111512
ISSN
1544-9173
DOI
10.1371/journal.pbio.1000097
language
English
LU publication?
yes
id
22e49328-be96-4bed-ad67-64a88b4e0cb3 (old id 1412859)
date added to LUP
2009-07-03 09:19:27
date last changed
2017-11-19 04:02:21
@article{22e49328-be96-4bed-ad67-64a88b4e0cb3,
  abstract     = {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.},
  author       = {Björk, Per and Björk, Anders and Vogl, Thomas and Stenström, Martin and Liberg, David and Olsson, Anders and Roth, Johannes and Ivars, Fredrik and Leanderson, Tomas},
  issn         = {1544-9173},
  language     = {eng},
  number       = {4},
  pages        = {800--812},
  publisher    = {Public Library of Science},
  series       = {PLoS Biology},
  title        = {Identification of human S100A9 as a novel target for treatment of autoimmune disease via binding to quinoline-3-carboxamides.},
  url          = {http://dx.doi.org/10.1371/journal.pbio.1000097},
  volume       = {7},
  year         = {2009},
}