Identification of human S100A9 as a novel target for treatment of autoimmune disease via binding to quinoline-3-carboxamides.
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1412859
- author
- Björk, Per ; Björk, Anders ; Vogl, Thomas ; Stenström, Martin ; Liberg, David ; Olsson, Anders ; Roth, Johannes ; Ivars, Fredrik LU and Leanderson, Tomas LU
- organization
- publishing date
- 2009
- type
- Contribution to journal
- publication status
- published
- subject
- in
- PLoS Biology
- volume
- 7
- issue
- 4
- pages
- 800 - 812
- publisher
- Public Library of Science (PLoS)
- external identifiers
-
- wos:000266500000009
- pmid:19402754
- scopus:65949111512
- pmid:19402754
- ISSN
- 1545-7885
- DOI
- 10.1371/journal.pbio.1000097
- language
- English
- LU publication?
- yes
- id
- 22e49328-be96-4bed-ad67-64a88b4e0cb3 (old id 1412859)
- date added to LUP
- 2016-04-01 15:01:17
- date last changed
- 2022-04-22 06:25:51
@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 = {{1545-7885}}, language = {{eng}}, number = {{4}}, pages = {{800--812}}, publisher = {{Public Library of Science (PLoS)}}, 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}}, doi = {{10.1371/journal.pbio.1000097}}, volume = {{7}}, year = {{2009}}, }