Immune cells use complex sugars called glycans to recognise other cells and find their correct site of activity. When this goes wrong, this can lead to under- or over-activation of the immune system and results in disease states like auto-immunity or poor clearance of cancer cells. One of the molecules that immune cells use for recognising glycans is the family of proteins called selectins. The three proteins in this family are present on different types of cells, such as the cells that make up blood vessels, and 'grab hold' of the immune cells when there is a problem, such as inflammation. This causes the immune cell to slow down in blood circulation, and escape into the surrounding tissue where they are needed. This interaction, between selectins on the surface of blood vessels and the glycans on immune cells, is therefore very important for targeting the immune system to its site of action.
The interaction between proteins and sugars is often weak, requiring many interactions to work together to give a strong effect. For this reason, it has been difficult to find molecules that can be used to target selectins. In this work, we investigated the interaction between selectins and glycans and tried to find molecules that can be used to disrupt the selectin-glycan interaction. These might eventually be useful in medicine, for example preventing chronic inflammation or stopping cancer cells from hijacking this adhesion process to spread throughout the body.
Our objectives were to find molecules that could bind strongly and selectively to each of the three selectins. To achieve this, we modified a system for generating tens of billions of different compounds at a time, with DNA used as a barcode to allow identification of which of these many different molecules can bind to the selectin. This required us to develop some new chemical tools to allow this pool of molecules to better resemble the glycans that selectins normally bind to, improving our chances of success. We also aimed to use this vast pool of different molecules to look for patterns of binding that might teach us more about how selectins work.
