A chemoselective ligation route to glycosyltransferase substrate mimetics

Lead Research Organisation: University of East Anglia
Department Name: Chemistry

Abstract

A detailed understanding of the innate workings of the cell is imperative for our prospects of making new advances in the treatment of infections and disease. How the cells of our body respond to stresses ranging from cancer to the common cold is all highly sought knowledge. To help reveal this information we intend to design a range of small chemical compounds which can get into the cells and shut down the function(s) of specific proteins in order to observe the effects on the cell and reveal the role of specific proteins in cell maintenance. This can be achieved by using chemicals which mimic the ones the proteins normally work with and use them to distract the protein from doing its proper job. We want to mimic sugar nucleotides (sugar-NDPs).Sugar-NDPs are the building blocks used by a class of intracellular biocatalytic proteins know as glycosyltransferases (GTs). GTs biosynthesise oligosaccharides and glycoproteins which are central players in cellular function and maintenance. Sugar-NDPs carry some 'fat-repelling' negative charge which stops them from escaping the cells' watery innards through the greasy cell membrane, but also prevents the delivery of sugar-NDP mimics into the cell. The ability to prepare uncharged sugar-NDP mimetics which can ultimately diffuse into cells and perturb the function of specific GTs would be extremely desirable. We will develop synthetic chemical methods that will facilitate the preparation of such sugar-NDP-like compounds by replacing the negatively charged component of the sugar-NDP (ie. the pyrophosphate group) with a sugar molecule. The sugar should be able to mimic the missing pyrophosphate component and also help to make the sugar-NDP mimic more greasy. This will increase its chances of getting into get into the cell across the greasy cell membrane to do the job at hand. Current methods for synthesising such molecules can be particularly challenging and time consuming. However we will design a selection of simple chemical building blocks that be chemically 'clipped' together in different combinations so that it will be possible to prepare a range of uncharged sugar-NDP-like structures in a less labour intensive manner.

Publications

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Related Projects

Project Reference Relationship Related To Start End Award Value
EP/D080304/1 01/07/2007 16/09/2007 £180,309
EP/D080304/2 Transfer EP/D080304/1 17/09/2007 16/08/2009 £159,797