Structure-based design of decoy chemokines as a way to explore the pharmacological potential of glycosaminoglycans - PubMed (original) (raw)

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Structure-based design of decoy chemokines as a way to explore the pharmacological potential of glycosaminoglycans

Tiziana Adage et al. Br J Pharmacol. 2012 Nov.

Abstract

Glycosaminoglycans (GAGs) are a class of highly negatively charged, unbranched, O-linked polysaccharides that are involved in many diseases. Their role as a protein-binding matrix on cell surfaces has long been recognized, but therapeutic approaches to interfere with protein-GAG interactions have been limited due to the complex chemistry of GAGs, on one hand, and due to the lack of specific antibodies against GAGs, on the other hand. We have developed a protein engineering platform (the so-called CellJammer(®) technology), which enables us to introduce higher GAG-binding affinity into wild-type GAG-binding proteins and to combine this with impaired biological, receptor-binding function. Chemokines are among the prototypic GAG-binding proteins and here we present selected results of our CellJammer technology applied to several of these proinflammatory proteins. An overview is given of our lead decoy protein, PA401, which is a CXCL8-based mutant protein with increased GAG-binding affinity and decreased CXCR1/2 binding and activation. Major results from our CCL2 and CCL5 programmes are also summarized and the potential for clinical application of these decoy proteins is presented.

© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

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Figures

Figure 1

Figure 1

Structures of the main glycosaminoglycans. HS, heparan sulfate; CS, chondroitin sulfate; DS, dermatan sulfate; KS, keratan sulfate.

Figure 2

Figure 2

Schematic representation of the CellJammer® approach for interfering with protein–glycosaminoglycan interactions.

Figure 3

Figure 3

Schematic representation of the presumed mode of action of CellJammer® proteins.

Figure 4

Figure 4

Model structure of PA508 docked to a heparin octasaccharide. Explicitly shown are the amino acid residues responsible for increased GAG-binding (green) and knocked-out CCR2 activation (blue). The structure for 1DOK.pdb (cf. P13500 UniProt) was used as the template for the model of the PA508 mutant. Heparin was placed in proximity to 21K and 23R of the PA508 model, using 1HPN.pdb as a model of heparin. The protein models were held rigid and the heparin polymer was minimized and adjusted to fit to the protein models. Using each individual protein model, further minimization accommodating side-chain relaxation was also performed. MMFF94 force field was used.

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References

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