Fully-functionalised probes for chemical proteomics

识别和探索新的与生物相关的化学空间是化学生物学和药物化学的一个主要挑战。随手可得的化学探针可以极大地影响实验研究的生物医学科学。然而，确定新的生物相关的化学空间受到生物和化学的不平衡探索的阻碍。尽管缺乏证据支持它们与疾病的特殊关联，但生物学家最喜欢的蛋白质在20多年里基本上没有改变。此外，生物活性小分子的发现仍然受到一个非常狭窄的反应工具包的支持，这限制了探索化学空间的支架多样性。那么，如何在表型、靶蛋白和生物活性化学型之间建立新的联系，以进一步加深我们对生物学的理解，并最终治疗疾病呢？该项目将专注于开发一锅合成各种小分子探针的方法，这些探针已经完全用于化学生物学研究。由此产生的探针将驻留在新的化学空间；将配备各种亲电弹头；并且将已经与可点击炔标签功能化。学生将展示这些不同的化学探针可以被用来解锁与生物相关的化学空间的新区域，并可能揭示细胞生物学机制的分子基础。这些工具可能为疾病的治疗提供新的治疗策略。具体目标是：1。1 .确定一锅化学探针合成可行的底物组合；使用一锅结缔组织化学制备一套多样化的全功能化探针。评估模型生物系统中的探针集

Identifying and exploring new biologically-relevant chemical space is a major challenge that is central to both chemical biology and medicinal chemistry. Readily-available chemical probes can dramatically influence the biomedical science that is investigated experimentally. Yet, identifying new biologically-relevant chemical space is hampered by the uneven exploration of both biology and chemistry. Biologists favourite proteins are largely unchanged for more than 20 years despite a lack of evidence supporting their particular relevance to disease. Moreover, bioactive small molecule discovery continues to be underpinned by a remarkably narrow reaction toolkit that limits the scaffold diversity of explored chemical space. How, then, can new connections between phenotypes, target proteins and bioactive chemotypes be established to further our understanding of biology and, ultimately, to treat disease?This project will focus on the development of approaches that enable the one-pot synthesis of diverse small molecule probes that are already fully-functionalised for chemical biology studies. The resulting probes will thus reside in novel chemical space; will be armed with diverse electrophilic warheads; and will already be functionalised with clickable alkyne tags. The student will demonstrate that these diverse chemical probes can be harnessed to unlock new regions of biologically-relevant chemical space, and may reveal insights into the molecular basis of cell biology mechanisms. These tools may unlock new therapeutic strategies for the treatment of disease.The specific objectives are:1. To identify viable substrate sets for one-pot chemical probe synthesis;2. To prepare a diverse set of fully-functionalised probes using one-pot connective chemistry3. To assess the probe set in model biological systems