A new platform called cPTM-display will mix synthetic chemistry with molecular biology to build vast libraries of chemically diverse cyclic peptides that can latch onto proteins. Current peptide discovery platforms can generate huge numbers of candidates, but they are chemically limited—most peptides in a library look alike. cPTM-display solves this by encoding chemical modifications directly into the peptide-building process, so each candidate can carry a wider range of functional groups, including post-translational modifications and covalent reactive groups. This matters because chemical probes—molecules that bind and modulate a specific protein—are essential tools for understanding fundamental biology and validating new drug targets. Yet probes exist for only a tiny fraction of the human proteome, and many proteins are too challenging for existing methods. If cPTM-display works, it could unlock probe development for those difficult targets, accelerating the global push to create tools for every cellular protein. That would give researchers a systematic way to study protein function in real time, and could ultimately speed up the identification of new drug targets for diseases where current treatments fall short.
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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.
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