Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Amino Acid Motifs / genetics
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / metabolism*
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Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
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Chemokines / chemistry
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Chemokines / genetics*
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Chemokines / metabolism*
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Chemokines / therapeutic use
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Humans
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Mutation
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Protein Binding
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Proteoglycans / antagonists & inhibitors*
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Proteoglycans / metabolism*
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Receptors, Chemokine / antagonists & inhibitors
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Receptors, Chemokine / deficiency
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Receptors, Chemokine / genetics*
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Receptors, G-Protein-Coupled / deficiency
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Receptors, G-Protein-Coupled / genetics
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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Recombinant Proteins / therapeutic use*
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Sequence Deletion*
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Chemokines
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Proteoglycans
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Receptors, Chemokine
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Receptors, G-Protein-Coupled
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Recombinant Proteins