After GluHUT - A New Era for Synthetic Carbohydrate Receptors

对于超分子化学家来说，水中碳水化合物的识别是一个出了名的棘手问题。糖是被羟基伪装起来的，所以很难与水溶液区分开来，这是结合的先决条件。它们也是微妙的变量，因此很难相互区分。2019年，Pi的团队报告了一种合成的葡萄糖受体，这是一种医学上最具相关性的单糖，超出了最乐观的预期。它们的“葡萄糖结合六聚体”(GluHUT)与葡萄糖结合，亲和力高，可与大多数天然受体相媲美，且几乎具有完美的选择性。GluHUT的知识产权被世界领先的胰岛素生产商诺和诺德(NN)收购，现在是旨在开发葡萄糖敏感型胰岛素(GSI)的开发计划的基础，GSI可能对糖尿病的治疗具有变革性。在GluHUT成功的基础上，我们提出了一个工作计划。首先，将以新的方式开发原始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。然后这些开关将被应用于能够对葡萄糖敏感的胰岛素释放的材料中。还将研究亲脂性GluHUT的“相转移”应用，特别是跨双层膜的葡萄糖转移的可能性，以及GluHUT核心将被用作催化葡萄糖衍生物的“人造酶”反应的基础。其次，借鉴GluHUT的经验，我们将寻求识别其他碳水化合物的靶标。具有去对称核心的类似物已被确定为糖与轴向羟基结合的候选化合物，并将通过与计算化学家的合作开发能够进行先验设计的先进软件。

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.