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Functional Glycomics Through Chemoenzymatic Synthesis

Project description

Chemoenzymatic technologies in functional glycomics research

Most proteins on the surface of cells are modified by covalently linked carbohydrates. The glycan structures on these glycoproteins serve as mediators for many physiological processes. However, there are no methods available to produce libraries of complex glycans to study the biological properties of glycan-binding proteins. The EU-funded SWEETPROMISE project will develop chemoenzymatic technologies to create collections of well-defined keratan sulfate oligosaccharides and O-acetylated sialosides which are poorly understood glycan classes. The resulting compounds will be employed to develop a glycan microarray to identify ligands for glycan-binding proteins. Biological properties of hits identified in the microarray screening will be examined using newly developed cellular arrays. SWEETPROMISE will focus on immuno-regulatory proteins and viruses that often exploit cell surface glycans for infectivity.

Objective

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.

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Coordinator

UNIVERSITEIT UTRECHT
Net EU contribution
€ 2 500 000,00
Address
Heidelberglaan 8
3584 CS Utrecht
Netherlands

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Region
West-Nederland Utrecht Utrecht
Activity type
Higher or Secondary Education Establishments
Links
Other funding
€ 0,00

Beneficiaries (1)