A chemoselective ligation route to glycosyltransferase substrate mimetics

糖基转移酶底物模拟物的化学选择性连接途径

• 批准号: EP/D080304/2
• 负责人: Christopher Hamilton
• 金额: --
• 依托单位: University of East Anglia
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FD080304%2F2
• 关键词: chemoselective; ligation; route; glycosyltransferase; substrate

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.

详细了解细胞的先天运作对于我们在治疗感染和疾病方面取得新进展的前景至关重要。我们身体的细胞如何应对从癌症到普通感冒等各种压力，这是一门备受关注的知识。为了帮助揭示这些信息，我们打算设计一系列小的化合物，它们可以进入细胞并关闭特定蛋白质的功能，以观察对细胞的影响并揭示特定蛋白质在细胞维护中的作用。这可以通过使用化学物质来实现，这些化学物质模仿蛋白质通常与之一起工作的化学物质，并使用它们来分散蛋白质的注意力，使其无法正常工作。我们想要模拟糖核苷酸（糖-NDP）。糖-NDP是一类被称为糖基转移酶（GT）的细胞内生物催化蛋白质所使用的构建模块。GT生物合成寡糖和糖蛋白，它们是细胞功能和维持的核心参与者。糖-NDP携带一些“脂肪排斥”负电荷，阻止它们通过油腻的细胞膜逃离细胞的含水内脏，但也阻止糖-NDP模拟物进入细胞。制备可最终扩散到细胞中并扰乱特定GT功能的不带电荷的糖-NDP模拟物的能力将是极其期望的。我们将开发合成化学方法，通过取代糖-NDP的带负电荷的组分（即，糖-NDP）来促进此类糖-NDP样化合物的制备。焦磷酸基团）与糖分子。糖应该能够模拟缺少的焦磷酸盐组分，并且还有助于使糖-NDP模拟物更油腻。这将增加它穿过油腻的细胞膜进入细胞的机会，完成手头的工作。目前用于合成此类分子的方法可能特别具有挑战性且耗时。然而，我们将设计一系列简单的化学结构单元，这些化学结构单元以不同的组合被化学地“夹”在一起，使得可以以劳动密集度较低的方式制备一系列不带电荷的糖-NDP样结构。