Developing chemokine mutants with improved proteoglycan affinity and knocked-out GPCR activity as anti-inflammatory recombinant drugs.
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.
Potzinger
H
H
Institute of Pharmaceutical Sciences, University of Graz, Austria.
Geretti
E
E
Brandner
B
B
Wabitsch
V
V
Piccinini
A-M
AM
Rek
A
A
Kungl
A J
AJ
D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D018925:Chemokines / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism* / Q000627:therapeutic use; D006801:Humans; D009154:Mutation; D011485:Protein Binding; D011509:Proteoglycans / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D017384:Sequence Deletion
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018925:Chemokines; D011509:Proteoglycans; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins