After GluHUT - A New Era for Synthetic Carbohydrate Receptors
Lead Research Organisation:
University of Bristol
Department Name: Chemistry
Abstract
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.
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.
