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Molecules 2014, 19(7), 10618-10634; doi:10.3390/molecules190710618

A Combinatorial Approach to Biophysically Characterise Chemokine-Glycan Binding Affinities for Drug Development

Institute of Pharmaceutical Sciences, Karl-Franzens-University Graz, Humboldtstrasse 46, A-8010 Graz, Austria
ProtAffin Biotechnologie AG, Reininghausstrasse 13a, A-802 Graz, Austria
Author to whom correspondence should be addressed.
Received: 22 May 2014 / Revised: 7 July 2014 / Accepted: 16 July 2014 / Published: 22 July 2014
(This article belongs to the Special Issue Oligosaccharides and Glyco-Conjugates)
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Chemokine binding to glycosaminoglycans (GAGs) is recognised to be an important step in inflammation and other pathological disorders like tumor growth and metastasis. Although different ways and strategies to interfere with these interactions are being pursued, no major breakthrough in the development of glycan-targeting drugs has been reported so far. We have engineered CXCL8 towards a dominant-negative form of this chemokine (dnCXCL8) which was shown to be highly active in various inflammatory animal models due to its inability to bind/activate the cognate CXCL8 GPC receptors on neutrophils in combination with its significantly increased GAG-binding affinity [1]. For the development of GAG-targeting chemokine-based biopharmaceuticals, we have established a repertoire of methods which allow the quantification of protein-GAG interactions. Isothermal fluorescence titration (IFT), surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), and a novel ELISA-like competition assay (ELICO) have been used to determine Kd and IC50 values for CXCL8 and dnCXCL8 interacting with heparin and heparan sulfate (HS), the proto-typical members of the GAG family. Although the different methods gave different absolute affinities for the four protein-ligand pairs, the relative increase in GAG-binding affinity of dnCXCL8 compared to the wild type chemokine was found by all methods. In combination, these biophysical methods allow to discriminate between unspecific and specific protein-GAG interactions. View Full-Text
Keywords: chemokines; fluorescence spectroscopy; glycosaminoglycans; heparan sulfate; surface plasmon resonance chemokines; fluorescence spectroscopy; glycosaminoglycans; heparan sulfate; surface plasmon resonance

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This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Gerlza, T.; Hecher, B.; Jeremic, D.; Fuchs, T.; Gschwandtner, M.; Falsone, A.; Gesslbauer, B.; Kungl, A.J. A Combinatorial Approach to Biophysically Characterise Chemokine-Glycan Binding Affinities for Drug Development. Molecules 2014, 19, 10618-10634.

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