Macrocyclic receptors for the recognition of biologically relevant substrates

用于识别生物学相关底物的大环受体

• 批准号: 315311-2013
• 负责人: Petitjean, Anne
• 金额: $ 2.48万
• 依托单位: Queen's University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=685292
• 关键词: Macrocyclic; receptors; recognition; biologically; relevant

Synthetic chemists have unique opportunities to create nanoscopic agents that interface with the biological world, detect and reveal events in cells, and provide insight into vital processes. In this context, our research program focuses on two types of synthetic agents for the detection of important DNA folds and DNA damage:(i) Guanine quadruplexes are important nucleic acid folds that are involved in cancer inception, proliferation and invasion. It is possible to prevent these events with interfering agents, provided they find their target in the cell. To achieve this goal, we are investigating macrocyclic ligands bearing a metal ion in their center. Such agents should select specific guanine quadruplexes and provide new tools to study the regulation of cancer-related events. Among all the metals we can choose from, we are excited by lanthanides as they should allow these agents to 'light-up' upon reaching their target. This is very useful to localize these agents and signal events in cells. A soft technology will be explored to facilitate the analysis of cells and tissues under mild conditions.(ii) DNA adducts generated by reaction with mutagens form before cancer appears. We want to understand how to detect these early events. Inspired by natural enzymes, we propose artificial pockets organized by metal ions where the adducts could fit. We will explore their capacity to recognize three main families of cancer-relevant DNA damage, and determine which features are most important for damage recognition. The work will be carried out by eight students who will be mentored on technical grounds (synthesis, spectroscopies, microscopies, biochemical, biophysical studies) and leadership grounds (collaborative work, integration within an international network). Research outcomes will benefit an interdisciplinary audience, from Biochemists and Biophysicists (parts A,C) to Physicists working on non-linear optics (Part B) and synthetic Chemists (all parts). Translation to industry is also anticipated with luminescent and/or electrochemical sensors.

合成化学家拥有独特的机会来创造与生物世界相互作用的纳米级试剂，检测和揭示细胞中的事件，并提供对生命过程的洞察。在此背景下，我们的研究计划重点关注两种类型的合成试剂，用于检测重要的 DNA 折叠和 DNA 损伤：(i) 鸟嘌呤四链体是参与癌症发生、增殖和侵袭的重要核酸折叠。只要干扰剂在细胞中找到目标，就有可能预防这些事件。为了实现这一目标，我们正在研究中心带有金属离子的大环配体。此类药物应选择特定的鸟嘌呤四链体，并为研究癌症相关事件的调控提供新工具。 在我们可以选择的所有金属中，我们对镧系元素感到兴奋，因为它们应该允许这些试剂在达到目标时“发光”。这对于定位细胞中的这些因子和信号事件非常有用。将探索一种软技术，以促进在温和条件下对细胞和组织进行分析。（ii）在癌症出现之前，与诱变剂反应产生的DNA加合物形成。我们想了解如何检测这些早期事件。受天然酶的启发，我们提出了由金属离子组织的人工口袋，可以容纳加合物。我们将探索它们识别与癌症相关的 DNA 损伤的三个主要家族的能力，并确定哪些特征对于损伤识别最重要。 这项工作将由八名学生进行，他们将在技术方面（合成、光谱学、显微镜、生物化学、生物物理研究）和领导力方面（协作工作、国际网络内的整合）得到指导。研究成果将使跨学科受众受益，从生物化学家和生物物理学家（A、C 部分）到从事非线性光学工作的物理学家（B 部分）和合成化学家（所有部分）。发光和/或电化学传感器也有望应用于工业领域。