Isolation and Characterization of Heparan Sulfate from Human Lung Tissues.

Glycosaminoglycans are a class of linear, highly negatively charged, -linked polysaccharides that are involved in many (patho)physiological processes. In vitro experimental investigations of such processes typically involve porcine-derived heparan sulfate (HS). Structural information about human, particularly organ-specific heparan sulfate, and how it compares with HS from other organisms, is very limited.

Development of Molecules Antagonizing Heparan Sulfate Proteoglycans.

Heparan sulfate proteoglycans (HSPGs) occur in almost every tissue of the human body and consist of a protein core, with covalently attached glycosaminoglycan polysaccharide chains. These glycosaminoglycans are characterized by their polyanionic nature, due to sulfate and carboxyl groups, which are distributed along the chain. These chains can be modified by different enzymes at varying positions, which leads to huge diversity of possible structures with the complexity further increased by varying chain lengths.

Preparation and Characterization of Glycosaminoglycan Chemokine Coreceptors.

Interactions between chemokines and glycosaminoglycans (GAGs) are crucial for the physiological and pathophysiological activities of chemokines. GAGs are therefore commonly designated as chemokine coreceptors which are deeply involved in the chemokine-signaling network. Studying the interaction of chemokines with GAGs is therefore a major prerequisite to fully understand the biological function of chemokines.

The Positively Charged COOH-terminal Glycosaminoglycan-binding CXCL9(74-103) Peptide Inhibits CXCL8-induced Neutrophil Extravasation and Monosodium Urate Crystal-induced Gout in Mice.

The ELR(-)CXC chemokine CXCL9 is characterized by a long, highly positively charged COOH-terminal region, absent in most other chemokines. Several natural leukocyte- and fibroblast-derived COOH-terminally truncated CXCL9 forms missing up to 30 amino acids were identified. To investigate the role of the COOH-terminal region of CXCL9, several COOH-terminal peptides were chemically synthesized.

Designing a mutant CCL2-HSA chimera with high glycosaminoglycan-binding affinity and selectivity.

Chemokines like CCL2 mediate leukocyte migration to inflammatory sites by binding to G-protein coupled receptors on the target cell as well as to glycosaminoglycans (GAGs) on the endothelium of the inflamed tissue. We have recently shown that the dominant-negative Met-CCL2 mutant Y13A/S21K/Q23R with improved GAG binding affinity is highly bio-active in several animal models of inflammatory diseases. For chronic indications, we have performed here a fusion to human serum albumin (HSA) in order to extend the serum half-life of the chemokine mutant.