The Inhibition of Glycosyltransferases as a Potential Therapeutic Target: It has been estimated that 2-3% of mammalian genomes are associated with the production of carbohydrate-processing proteins and enzymes. Of these by far the most widespread class of such proteins are glycosyltransferases (GlyTs). This remarkable but poorly understood class of enzymes are ubiquitous in nature and play a wide range of fundamental biological roles in events as diverse as fertilization, cancer, immunology, cell signalling and protein folding. Importantly, certain types that perform highly specific functions associated with disease states have been identified and offer themselves as potential targets for inhibition. Yet, to date few potent and specific inhibitors of any of the many thousand of potential enzyme targets have been identified. None are in development as drugs. We aim to develop and apply recent chemical discoveries in our laboratory for the construction of sugar mimetics to the creation of a new generation of mu lticomponent inhibitors of GlyTs. By using such a component assembly approach, we will design and optimize mimetic modules that will fit key binding pockets of these enzymes. In this way we will not only develop an improved understanding of this class of e nzymes but will also use this understanding to create potent inhibitors. As directly relevant GlyTs of high potential therapeutic utility, we have chosen to target Mycobacterial GlyTs as model systems in which to explore this novel but general modular meth odology that we believe will allow ready adaptation to other, important GlyT targets, such as e.g., fucosyltransferases. If successful this programme would therefore not only create leads of potential utility in the treatment of tuberculosis but methodolo gy applicable to other diseases associated with GlyTs e.g. mycocardial infarction and cancer metastasis.
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