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

化学探针提供了一种以时间和上下文相关的方式调节蛋白质功能的强大途径，为基础生物学提供了新的见解，并提供了验证新药物靶点的工具。为了最大限度地发挥它们对生物学的影响，到2035年，全球都在雄心勃勃地开发出对抗所有细胞蛋白质的工具。由于目前探针只占蛋白质组的4%，为了实现这一目标，迫切需要新的广泛适用的策略来识别新的探针。在这项提案中，我将开发cPTM Display，一个环肽发现平台，并将其应用于一系列治疗相关蛋白质的探测发现。CPTM Display将结合使用最先进的多肽发现平台(如mRNA Display)可以实现的巨大文库大小，以及可以使用合成化学方法获得的更大的化学多样性。我将探索可以在cPTM显示中编码的不同模板化化学转换的范围，以及可以转移到多肽的化学翻译后修饰(CPTM)的全部范围。合成的化学多样性环肽文库将被用于开发针对参与调节生物PTMS的治疗相关蛋白的新的化学探针。除了化学探针的开发，文库还将用于探索细胞的PTM靶向。然后，cPTM显示将进一步扩展到发现与其目标发生共价反应的多肽。通过将有机合成和分子生物学结合在一起，cPTM Display将使我们开发化学多样性环肽的能力发生重大变化，即使是最具挑战性的蛋白质靶标也能进行化学探针开发。

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.