Transforming high-throughput screening of extracellular receptor interactions using miniaturised, label-free photonic sensor arrays

Signalling between cells is of fundamental biological importance and involves interactions between molecular messengers and receptor proteins located at the cell surface. These cell surface receptors are also used by pathogens such as viruses and parasites, to recognise and invade our cells, and are a target for new antibody-based treatments for conditions such as cancer and autoimmune diseases. Obtaining a systematic, whole-organism view of these interactions would allow us to better understand the function of these important proteins, support early identification of zoonotic pathogens (pathogens known to infect animals that have evolved to infect humans), and support the discovery of new treatments. However, the chemical properties of these cell surface receptor proteins makes them difficult to produce and to study. We have shown a solution to this problem - rather than make the whole protein, we only make the part that extends beyond the cell wall (the ectodomain) that provides the important, binding function. This approach has now allowed us to make >1500 different ectodomains which represents the majority of tractable human receptor proteins. Although we now have access to this large number of proteins, the technologies used to measure their interactions can still only measure a limited number of proteins, use large amounts of expensive materials, and important information such as the rate (kinetics) and interaction strength cannot be determined.

To address these limitations, we will capitalise on new advances in optical physics to deliver a step-change in the ability to study the many, diverse receptor protein interactions.

We build on pioneering research in miniaturised optical sensors that can directly detect and quantify the kinetics and strength of protein interactions. And not just one protein. These sensors can be miniaturised to measure many proteins - potentially thousands - all at the same time. Here we will combine this technological innovation with our unique library of >1500 receptor proteins to create a miniaturised array of optical sensors, where each sensor in the array examines a different human receptor protein. The sensors will characterise each receptor in parallel, allowing us to systematically identify which proteins interact with which receptor and immediately measure the strength of interaction. We will demonstrate this transformative technology to study the way viruses (e.g. coronavirus) and parasites (e.g. malaria) interact with human cells. We will then give colleagues from multiple areas of biology access to this radical innovation and support them to study their own research problems.