The interaction of chemokines and GAGs (glycosaminoglycans) on endothelial surfaces is a crucial step for establishing a chemotactic gradient which leads to the functional presentation of chemokines to their GPCRs (G-protein-coupled receptors) and thus to activation of approaching leucocytes. Based on molecular modelling, biophysical investigations, cell-based and in vivo experiments, we have developed a novel concept for therapeutically interfering with chemokine–GAG interactions, namely dominant-negative chemokine mutants with improved GAG binding affinity and knocked-out GPCR activity. These recombinant proteins displace their wild-type chemokine counterparts from the natural proteoglycan co-receptors without being able to activate leucocytes via GPCRs. Our mutant chemokines therefore represent the first protein-based GAG antagonists with high therapeutic potential in inflammatory diseases.
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June 2006
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Conference Article|
May 22 2006
Developing chemokine mutants with improved proteoglycan affinity and knocked-out GPCR activity as anti-inflammatory recombinant drugs
H. Potzinger;
H. Potzinger
*Institute of Pharmaceutical Sciences, University of Graz, A-8010 Graz, Austria
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E. Geretti;
E. Geretti
1
*Institute of Pharmaceutical Sciences, University of Graz, A-8010 Graz, Austria
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B. Brandner;
B. Brandner
*Institute of Pharmaceutical Sciences, University of Graz, A-8010 Graz, Austria
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V. Wabitsch;
V. Wabitsch
†ProtAffin Biotechnologie AG, A-8020 Graz, Austria
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A.-M. Piccinini;
A.-M. Piccinini
†ProtAffin Biotechnologie AG, A-8020 Graz, Austria
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A. Rek;
A. Rek
*Institute of Pharmaceutical Sciences, University of Graz, A-8010 Graz, Austria
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A.J. Kungl
A.J. Kungl
2
*Institute of Pharmaceutical Sciences, University of Graz, A-8010 Graz, Austria
†ProtAffin Biotechnologie AG, A-8020 Graz, Austria
2To whom correspondence should be addressed (email andreas.kungl@uni-graz.at).
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Biochem Soc Trans (2006) 34 (3): 435–437.
Article history
Received:
January 10 2006
Citation
H. Potzinger, E. Geretti, B. Brandner, V. Wabitsch, A.-M. Piccinini, A. Rek, A.J. Kungl; Developing chemokine mutants with improved proteoglycan affinity and knocked-out GPCR activity as anti-inflammatory recombinant drugs. Biochem Soc Trans 1 June 2006; 34 (3): 435–437. doi: https://doi.org/10.1042/BST0340435
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