Bicyclic peptides are an exciting class of molecular tools that are transforming the way researchers study biology. Unlike traditional small molecules, bicyclic peptides can bind tightly and selectively to complex protein surfaces, making them particularly powerful for probing protein-protein interactions, which control many fundamental cellular processes. As chemical tools, they allow us to investigate biological mechanisms that have previously been difficult to access, providing new insights into how proteins communicate and function within cells.
A major challenge in the field is understanding exactly how bicyclic peptides influence protein interactions and how binding at different sites of the protein can lead to distinct biological outcomes. To address this question, the project will focus on an important biological system: the complement cascade, a key part of the body's innate immune defence.
The complement system comprises over 30 proteins working together to identify and eliminate pathogens. Increasing evidence suggests that dysregulation of complement contributes to a wide range of diseases, including inflammatory disorders and neurodegenerative diseases. Understanding how complement proteins function and communicate is therefore a fundamental question in modern immunology and cell biology.
At the centre of this network is complement C5, a molecular hub that activates the membrane attack complex, the final stage of the complement response. Through a long-standing industry collaboration with Bicycle Therapeutics, we have identified a unique collection of bicyclic peptides that bind to multiple distinct regions of C5, including several sites that have never been explored before. These molecules provide a toolkit for dissecting how different regions of C5 regulate immune signalling and biological function.
Through this inter-disciplinary project, the student will visualise how peptides interact with C5 at atomic-level detail using cryo-electron microscopy, measure protein-protein interactions using a series of biophysical techniques, investigate the biological consequences of targeting C5 in cells, and integrate experimental data with machine learning to rationalise new peptide design.
You will receive training in state-of-the-art technologies at the interface of biology and chemistry, through working closely with academic and industrial scientists, to address fundamental questions about how the immune system operates. Through precision molecular tools, this project offers the opportunity to discover how molecules control life processes to understand the biology behind human health.
Find more details and how to apply here.
