Expanding the biological diversity of chemical probes to ligand the 'dark' proteome

扩大化学探针的生物多样性以配体“暗”蛋白质组

• 批准号: 2883062
• 金额: --
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2883062
• 关键词: Expanding; biological; diversity; chemical; probes

Identifying and exploring new biologically-relevant chemical space is a major challenge, central to both chemical biology and medicinal chemistry. Access to high quality chemical probes dramatically influences the scope of experimentally-investigated biomedical science and is crucial for validating novel targets. Small molecule drugs continue to dominate our collective ability to treat disease, yet identifying new biologically-relevant chemical space is hampered by the dominance of a narrow reaction toolkit. With the advent of reactive fragments, and the powerful companion technology of chemical proteomics, we now envision the prospect of mapping biological coverage systematically in a native cellular context. In this project, we will develop connective reactions that enable the one-pot, plate-based synthesis of diverse sets of distinctive reactive fragments (RFs). The synthetic approach will contrast starkly with the typical multi-step synthesis of fully-functionalised probes; as well as the simple amide coupling chemistry that generally drives direct-to-biology experimentation. To broaden explorable chemical space, prioritised chemistries lie outside the reaction toolkit that currently dominates discovery. Furthermore, to complement existing cysteine-directed RF sets, we will deliberately exploit electrophilic "warheads" with distinctive (particularly lysine-directed) reactivity. Having established this capability, we will: (a) investigate extension of direct-to-biology experimentation beyond amide coupling chemistry; and (b) execute biological mapping of the distinctive RFs using chemical proteomics and machine learning. We will thus demonstrate that diverse RF sets, accessible via the new chemistries, can enable liganding of the "dark" proteome.

识别和探索新的生物相关化学空间是一项重大挑战，是化学生物学和药物化学的核心。获得高质量的化学探针极大地影响了实验研究的生物医学科学的范围，对于验证新目标至关重要。小分子药物继续主导着我们治疗疾病的集体能力，但识别新的生物相关化学空间受到狭窄反应工具包主导地位的阻碍。随着反应性片段的出现，以及化学蛋白质组学的强大配套技术，我们现在设想了在天然细胞背景下系统地绘制生物覆盖范围的前景。在这个项目中，我们将开发连接反应，使一锅，板为基础的不同套独特的反应片段（RF）的合成。该合成方法将与典型的全功能化探针的多步合成形成鲜明对比;以及通常驱动直接生物实验的简单酰胺偶联化学。为了拓宽可探索的化学空间，优先化学位于目前主导发现的反应工具包之外。此外，为了补充现有的半胱氨酸定向RF集，我们将故意利用亲电子“弹头”具有独特的（特别是赖氨酸定向）反应性。在建立了这种能力之后，我们将：（a）研究直接生物实验的扩展超出酰胺偶联化学;（B）使用化学蛋白质组学和机器学习对独特的RF进行生物作图。因此，我们将证明，不同的RF集，可通过新的化学，可以使配位的“黑暗”的蛋白质组。