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.

水溶液中碳水化合物的识别一直是超分子化学家们难以解决的难题。双酰胺被羟基包裹，因此难以与水溶剂区分，而水溶剂是结合的先决条件。它们也有微妙的变化，因此很难相互区分。2019年，PI的团队报告了一种葡萄糖的合成受体，这是医学上最相关的单糖，超出了最乐观的预期。他们的“葡萄糖结合六脲寺”（GluHUT）结合葡萄糖具有高亲和力，可与大多数天然受体相媲美，几乎完美的选择性。GluHUT的知识产权被世界领先的胰岛素生产商诺和诺德公司（NN）收购，现在支持一项针对葡萄糖敏感胰岛素（GSI）的开发计划，该计划可能会改变糖尿病的治疗。在此，我们提出了一项建立在GluHUT成功基础上的工作计划。首先，将以新的方式利用原始GluHUT核心的葡萄糖结合特性。葡萄糖敏感开关将被设计成以受控的方式打开，模仿胰腺对葡萄糖浓度的反应。这些开关将被应用于葡萄糖敏感胰岛素释放材料。还将研究亲脂性GluHUT的“相转移”应用，特别是葡萄糖跨双层膜转运的潜力，并且GluHUT核心将用作“人工酶”催化葡萄糖衍生物反应的基础。第二，借鉴GluHUT的经验，我们将继续识别其他碳水化合物靶点。具有去对称核心的类似物已被确定为与轴向OH结合的候选物，并将通过与计算化学家合作开发能够进行先验设计的高级软件。