cPTM-display: An encoded platform for the identification of chemically diverse cyclic peptides

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Chemical probes provide a powerful route to modulate protein function in a time- and context-dependent manner, providing new insights into basic biology and tools to validate new drug targets. To maximise their impact on biology, there isa global ambition to develop tools against all cellular proteins by 2035. With probes to as little as 4% of the proteome currently, to achieve this goal there is an urgent need for new widely applicable strategies to identify new probes. In this proposal I will develop cPTM display, a cyclic peptide discovery platform, and apply it to probe discovery for a range of therapeutically relevant proteins. cPTM display will combine the massive library sizes that can be achieved using state-of-the-art peptide discovery platforms like mRNA display, with the much greater chemical diversity that can be accessed using synthetic chemistry. I will explore the range of different templated chemical transformations that can be encoded in cPTM display and the full scope of chemical post-translational modifications (cPTMs) that can be transferred to peptides. Resultant libraries of chemically diverse cyclic peptides will be applied to developing new chemical probes against therapeutically relevant proteins involved in the regulation of biological PTMs. In addition to chemical probe development, libraries will also be used to explore cellular PTM targeting. cPTM display will then be further expanded to the discovery of peptides that react covalently with their target. By combining aspects of organic synthesis and molecular biology, cPTM display will deliver a step change in our ability to develop chemically diverse cyclic peptides, enabling chemical probe development even for the most challenging protein targets.