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

识别和探索新的与生物相关的化学空间是一个重大挑战，对化学生物学和药物化学来说都是核心。获得高质量的化学探针极大地影响了经过实验调查的生物医学科学的范围，对于验证新的靶标至关重要。小分子药物继续主导着我们治疗疾病的集体能力，然而，由于狭义反应工具包的主导地位，识别新的生物相关化学空间受到阻碍。随着活性片段的出现，以及强大的化学蛋白质组学配套技术，我们现在展望了在自然细胞背景下系统地绘制生物覆盖图的前景。在这个项目中，我们将开发连接反应，使一锅，基于平板的不同组不同的反应片段(RF)的合成成为可能。这种合成方法将与典型的全功能化探针的多步骤合成形成鲜明对比；以及通常推动直接针对生物实验的简单的酰胺偶联化学。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导向射频装置，我们将故意利用具有独特(特别是赖氨酸导向)反应性的亲电“弹头”。在建立了这一能力后，我们将：(A)研究将直接到生物学的实验扩展到酰胺偶联化学之外；以及(B)使用化学蛋白质组学和机器学习来执行独特的RFs的生物图谱。因此，我们将证明，通过新的化学方法可以获得不同的RF组，可以使“暗”蛋白质组连接起来。

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.