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Functional Glycomics Through Chemoenzymatic Synthesis

Projektbeschreibung

Chemoenzymatische Technologien in der funktionellen Glykomikforschung

Die meisten Proteine auf der Oberfläche der Zellen werden durch kovalent gebundene Kohlenhydrate modifiziert. Die Glykanstrukturen auf diesen Glykoproteinen vermitteln viele physiologische Prozesse. Es stehen jedoch keine Verfahren zur Herstellung von Bibliotheken komplexer Glykane zur Verfügung, um die biologischen Eigenschaften glykanbindender Proteine zu erforschen. Das EU-finanzierte Projekt SWEETPROMISE wird chemoenzymatische Technologien entwickeln, um Sammlungen klar definierter Keratansulfat-Oligosaccharide und O-acetylierter Sialoside zu erstellen, die zu den noch nicht ausreichend erforschten Glykanklassen zählen. Die resultierenden Verbindungen werden zur Entwicklung eines Glykan-Mikroarrays eingesetzt, der Liganden für glykanbindende Proteine erkennen soll. Die biologischen Eigenschaften der im Mikroarray-Screening identifizierten Treffer werden mithilfe neu entwickelter Zell-Arrays untersucht. SWEETPROMISE wird sich auf immunregulatorische Proteine und Viren konzentrieren, die häufig auf der Zelloberfläche angesiedelte Glykane für ihre Infektiosität ausnutzen.

Ziel

Almost all cell surface proteins are modified by covalently-linked carbohydrates and the glycan structures on these glycoproteins are mediators of many physiological and disease processes. Despite their importance, there are no methods available to systematically and efficiently produce libraries of complex glycans to investigate specificities and biology of glycan binding proteins. To address this deficiency, we will develop chemoenzymatic technologies that can provide large collections of glycans having architectures of unprecedented complexity. It will exploit chemically modified sugar nucleotide donors that can be transferred by glycosyl transferases to give products in which artificial entities will blocks specific sites from enzymatic modification. It will provide full control over branching, sites of fucosylation, sulfation and sialylation. The chemical entities will be chosen in such a way that they can be removed after a series of enzymatic transformations. The methodology will be employed to prepare a series of keratan sulfate oligosaccharides. These glycoconjugates, which are biologically still poorly understood, have been implicated a multitude of physiological and disease processes. To further broaden the scope of the technology, a chemoenzymatic methodology will be developed to prepare sialosides that at C-4, C-7, C-8 and/or C-9 are modified by acetyl esters. The compounds will be used to develop a designer glycan microarray to identify ligands for glycan binding proteins. The focus will be on immuno-regulatory proteins and viruses that exploit cell surface glycans for infectivity. Cellular arrays will be developed to examine biological properties of hits identified in the microarray screening. The results of the studies will provide critical insight about glycan complexity and recognition by self- and viral glycan binding proteins, and will provide leads for the development of immune-modulators and antiviral agents.

Finanzierungsplan

ERC-ADG - Advanced Grant

Gastgebende Einrichtung

UNIVERSITEIT UTRECHT
Netto-EU-Beitrag
€ 2 500 000,00
Adresse
HEIDELBERGLAAN 8
3584 CS Utrecht
Niederlande

Auf der Karte ansehen

Region
West-Nederland Utrecht Utrecht
Aktivitätstyp
Higher or Secondary Education Establishments
Links
Gesamtkosten
€ 2 500 000,00

Begünstigte (1)