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Investigating selectin-glycopeptide interactions

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. We  are investigating the interaction between selectins and glycans to try 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 are to find molecules that could bind strongly and selectively to each of the three selectins. To achieve this, we are using a simple sugar moiety as a 'warhead' to target binding of a peptide library to the glycan binding site of selectins. Additional functional groups provided by the peptide will hopefully allow us to find tight binding macrocyclic thioglycopeptides that are selective for each selectin.

We are grateful for funding support for this project, provided by the European Union’s Horizon 2020 research and innovation programme under the Marie SkÅ‚odowska-Curie grant agreement No. 746631.

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