After GluHUT - A New Era for Synthetic Carbohydrate Receptors

GluHUT 之后——合成碳水化合物受体的新时代

• 批准号: EP/Y027779/1
• 负责人: Anthony Davis
• 金额: $ 269.36万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FY027779%2F1
• 关键词: After; GluHUT; New; Era; Synthetic

Carbohydrate recognition in water is a notoriously intractable problem for supramolecular chemists. Saccharides are camouflaged byhydroxyl groups, so are difficult to distinguish from aqueous solvent, the prerequisite for binding. They are also subtly variable, thusdifficult to distinguish from each other. In 2019, the PI's group reported a synthetic receptor for glucose, the most medically relevantmonosaccharide, which exceeded the most optimistic expectations. Their "Glucose-Binding Hexaurea Temple" (GluHUT) boundglucose with high affinity, comparable to most natural receptors, and almost perfect selectivity. The intellectual property for GluHUTwas acquired by Novo Nordisk (NN), the world's leading insulin producer, and now underpins a development programme aimed atglucose-sensitive insulin (GSI), potentially transformative for the treatment of diabetes.Here we propose a programme of work which builds on GluHUT's success. Firstly the glucose-binding properties of the originalGluHUT core will be exploited in new ways. Glucose-sensitive switches will be engineered to open in a controlled fashion, mimickingthe response of the pancreas to glucose concentrations. These switches will then be applied in materials capable of glucose-sensitiveinsulin release. "Phase transfer" applications of lipophilic GluHUTs will also be investigated, especially the potential for glucosetransport across bilayer membranes, and the GluHUT core will be used as the basis for "artificial enzymes" catalysing reactions ofglucose derivatives. Secondly, drawing on lessons from GluHUT, we will pursue the recognition of other carbohydrate targets.Analogues with desymmetrised cores have been identified as candidates for binding saccharides with axial OH, and advancedsoftware enabling a priori design will be developed through collaboration with computational chemists.

对于超分子化学家来说，水中的碳水化合物识别是一个棘手的问题。羟基被羟基伪装，因此很难与水溶液区分开，这是结合的先决条件。它们也是微妙的变量，因此彼此区分。 2019年，PI组报告了葡萄糖的合成受体，葡萄糖是医学上最相关的单糖，它超出了最乐观的期望。他们的“葡萄糖结合六角形寺庙”（Gluhut）具有高亲和力，与大多数天然受体相当，几乎是完美的选择性。全球领先的胰岛素生产国Novo Nordisk（NN）收购的Gluhutwas的知识产权，现在是针对Atglucose敏感胰岛素（GSI）的开发计划的基础。首先，将通过新的方式利用原始gluhut核心的葡萄糖结合特性。葡萄糖敏感的开关将被设计为以受控方式打开，模仿胰腺对葡萄糖浓度的反应。然后，这些开关将应用于能够释放葡萄糖敏感性辛氨基蛋白的材料中。还将研究亲脂性Gluhuts的“相转移”应用，尤其是跨双层膜的葡萄糖术运动的潜力，Gluhut核心将用作“人工酶”催化反应的基础。其次，在Gluhut的课程上，我们将追求对其他碳水化合物靶标的识别。与对称核心的分析已被确定为用轴向OH结合糖的候选者，并且将通过与计算化学家协作来开发先验设计的高级施工。