Expanding the druggable proteome of immune cells - towards synthetic immune regulation (360G-Wellcome-210890_Z_18_Z)

Drugs capable of manipulating the innate immune system have the potential to treat a broad spectrum of human diseases. However, to realise this potential, we need both a better understanding of the biological processes that regulate innate immunity and to radically expand the scope of potentially druggable protein targets. My research will address both these limitations. I will use activity-based protein profiling to identify proteome-wide sites of ligandability in primary human immune cells and drive the development of frontier chemical probes, which can be used to dissect the principles of immune regulation or provide leads for drug development. In particular, my research will focus on proteins involved in non-degradative ubiquitylation, a critical pathway mediating signal transduction in innate immunity. My specific aims are to: Map the interactions of small molecules with proteins in primary human innate immune cells on a proteome-wide scale. Develop targeted mass spectrometry and synthetic biology platforms to efficiently verify, establish structure-activity relationships and explore the functional consequences of small molecule-protein interactions. Develop high-quality chemical probes for proteins that play critical roles in innate immunity. This research will provide the scientific community with the resources to embark on a new era of targeted immunotherapy.