Diversity-driven supramolecular and systems chemistry for biological applications

用于生物应用的多样性驱动的超分子和系统化学

• 批准号: RGPIN-2019-04806
• 负责人: Hof, Fraser
• 金额: $ 6.85万
• 依托单位: University of Victoria
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=737872
• 关键词: Diversity; driven; supramolecular; systems; chemistry

The Hof research program develops supramolecular binding agents for biological targets in water and other highly competitive solutions. These molecules are unconventional by most views of medicinal and biological chemistry. `Supramolecular binding agents' aren't like drugs or like proteins-they are large, concave, synthetic molecules that describe a binding pocket intended to recognize and bind other molecules. Our program aims to create molecules that will be immediately useful in various applications, and also to uncover fundamental new lessons about how molecules behave in solution. We will create new molecules with new functions that are important in multiple chemical and biological research settings. One set of our applied long-term goals involve creating rapid measurements of biomolecule concentrations and activities (e.g. drug tests, metabolite tests). Nature is salty, and we've learned in recent years how natural salts and other interfering molecules in solution can complicate the creation of successful host molecules. Stimulated by these challenges, we are opening a new track of basic research in which we pursue new fundamental knowledge about the impact of structure, solvent, and solute effects on aqueous molecular recognition. We hope to learn about how natural biomolecular recognition events can tolerate extreme solute concentrations. In the long run, these lessons will feed back into our applied projects, opening avenues for the creation of new salt-tolerant reagents. We are developing new methods on two tracks: molecular diversity and systems chemistry. In the first track, we are introducing new methods to rapidly make and test host molecules for a given property. Some are focused collections of dozens of molecules that explore a novel, biologically compatible (i.e. salt-tolerant) sensing mechanism that we recently invented. Other diversity projects involve new approaches that will allow us to create and test billions of hosts at a time. In the second track, we are inventing ways to create complex adaptive systems made up of dynamic mixtures of host molecules. These have relatively few individual molecules, but they are incredibly complex because they form networks of dynamic connections that change in response to different solution conditions and in response to added analytes. They are designed so the networks can adapt and change themselves in order to achieve a specific task in molecular sensing. In both areas we focus on developing methods that allow rapid synthesis and testing, so that we can quickly identify promising molecules without having to custom-design a host molecule for each and every binding target that might interest us. By taking innovative, method-development approaches, we are creating science that will have a broad impact beyond the individual molecules that we make, and we are also training students who can make their own future impacts in diverse areas of chemical, biology, and biotechnology.

霍夫研究计划为水中的生物目标和其他竞争激烈的解决方案开发超分子结合剂。从药物和生物化学的大多数观点来看，这些分子都是非常规的。“超分子结合剂”不像药物或蛋白质--它们是大的、凹的、合成的分子，描述了一个旨在识别和结合其他分子的结合袋。我们的计划旨在创造在各种应用中立即有用的分子，并揭示分子在溶液中如何表现的基本新课程。我们将创造具有新功能的新分子，这些新功能在多种化学和生物研究环境中都很重要。我们的一套应用的长期目标包括创建生物分子浓度和活动的快速测量(例如，药物测试、代谢物测试)。大自然是咸的，近年来我们已经了解到，天然盐和溶液中的其他干扰分子如何使成功的宿主分子的创建复杂化。在这些挑战的刺激下，我们正在开辟一条基础研究的新轨道，在其中我们追求关于结构、溶剂和溶质效应对水分子识别的影响的新的基础知识。我们希望了解自然生物分子识别事件如何耐受极端的溶质浓度。从长远来看，这些经验教训将反馈到我们的应用项目中，为创造新的耐盐试剂开辟道路。我们正在两个方面开发新的方法：分子多样性和系统化学。在第一个轨道中，我们正在引入新的方法来快速制造和测试给定性质的宿主分子。其中一些是由数十个分子组成的集中集合，探索我们最近发明的一种新颖的、生物兼容(即耐盐性)的传感机制。其他多样性项目涉及新的方法，使我们能够一次创建和测试数十亿个主机。在第二个轨道中，我们正在发明由宿主分子的动态混合物组成的复杂适应系统的方法。它们的单个分子相对较少，但它们极其复杂，因为它们形成了动态连接的网络，随着不同的溶液条件和添加的分析物而变化。它们的设计使网络能够自我适应和改变，以实现分子传感中的特定任务。在这两个领域，我们专注于开发能够快速合成和测试的方法，这样我们就可以快速识别有希望的分子，而不必为我们可能感兴趣的每个结合目标定制设计宿主分子。通过采用创新的方法开发方法，我们正在创造将产生广泛影响的科学，这些影响将超出我们制造的单个分子，我们还在培训能够在化学、生物和生物技术的不同领域产生未来影响的学生。