Developing a platform for conformational sensing of gut hormones in diagnosis and drug discovery

Gut-derived peptide hormones regulate a large number of important metabolic processes, and there is great interest in exploiting their effects to treat disease. The blockbuster anti-obesity agent semaglutide, based on modifications of the gut hormone glucagon-like peptide-1 (GLP-1), exemplifies this approach. Blood levels of several gut hormones are also used as biomarkers for the diagnosis and monitoring of neuroendocrine tumours, a group of rare cancers characterised by high levels of aberrant hormone secretion. Our laboratory is focussed on both gut hormones in both these contexts: we have had considerable success developing gut hormone-based drug candidates (five have entered phase I trials in the last decade and two are currently in phase II).

The aim of this project is to develop a novel platform for detecting gut hormones by coupling their target receptors to a fluorescence-based readout known as a conformational biosensor. This approach is based on the principle that receptors undergo conformational (shape) changes when they are activated by a ligand, and has been used to detect GLP-1, dopamine and other ligands (1,2). We hope to develop a platform based on this technology for quantifying the amount of selected gut hormones present in plasma samples, e.g. to aid diagnosis of gut hormone-producing tumours. Additionally, we have found that conformational sensors are able to provide unique information about the pharmacological characteristics of novel ligands, e.g. linked to “biased agonism”, a paradigm in which different agonists for the same receptor can show different preferences for downstream signalling pathways (3,4). We would like to integrate this technology into drug development projects underway in the laboratory that target metabolically relevant GPCRs.

This project is expected to consist of three main elements: 1) design and testing of in vitro fluorescence biosensors; 2) application to detection of gut hormones in plasma samples; and 3) application to characterise novel ligands being developed for therapeutic purposes. The student will be trained in modern pharmacological in vitro techniques, including cell-based signalling assays, high-throughput and high-resolution fluorescence microscopy. The drug development element of the project will include in vivo work in mouse models.  The broad range of techniques and strong translational application will provide a strong platform for a future career in academia or industry.

Potential applicants with a strong background in pharmacology, molecular biology, biochemistry, assay development, or related subjects are encouraged to contact Ben Jones to discuss the project (ben.jones@imperial.ac.uk).