A synthetic molecule that grabs glucose out of water with near-perfect precision is now being turned into a switch that could mimic the pancreas. The original “glucose-binding hexaurea temple” (GluHUT), reported in 2019, binds glucose as tightly as natural proteins do and ignores other sugars almost entirely. Novo Nordisk, the world’s largest insulin producer, has already bought the rights and is using it to develop glucose-sensitive insulin. The problem is that current insulin injections do not adjust to changing blood sugar levels. Patients must constantly monitor and dose themselves, risking dangerous highs and lows. This project aims to build glucose-sensitive switches that open only when glucose is present, then release insulin in a controlled, pancreas-like fashion. The same molecular core will also be tested for transporting glucose across cell membranes and for catalysing reactions on glucose derivatives. If successful, the work could lead to insulin that activates only when needed, transforming diabetes management. Beyond that, the team will use lessons from GluHUT to design synthetic receptors for other medically important sugars, supported by new computational tools for a priori design. This is applied supramolecular chemistry with a clear therapeutic target.
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Carbohydrate recognition in water is a notoriously intractable problem for supramolecular chemists. Saccharides are camouflaged by hydroxyl groups, so are difficult to distinguish from aqueous solvent, the prerequisite for binding. They are also subtly variable, thus difficult to distinguish from each other. In 2019, the PI's group reported a synthetic receptor for glucose, the most medically relevant monosaccharide, which exceeded the most optimistic expectations. Their "Glucose-Binding Hexaurea Temple" (GluHUT) bound glucose with high affinity, comparable to most natural receptors, and almost perfect selectivity. The intellectual property for GluHUT was acquired by Novo Nordisk (NN), the world's leading insulin producer, and now underpins a development programme aimed at glucose-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 original GluHUT core will be exploited in new ways. Glucose-sensitive switches will be engineered to open in a controlled fashion, mimicking the response of the pancreas to glucose concentrations. These switches will then be applied in materials capable of glucose-sensitive insulin release. "Phase transfer" applications of lipophilic GluHUTs will also be investigated, especially the potential for glucose transport across bilayer membranes, and the GluHUT core will be used as the basis for "artificial enzymes" catalysing reactions of glucose 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 advanced software enabling a priori design will be developed through collaboration with computational chemists.
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