New Molecules, Methods, and Platforms at the Interface of Organic Chemistry and Chemical Biology

有机化学和化学生物学交叉领域的新分子、方法和平台

• 批准号: RGPIN-2020-05461
• 负责人: Perrin, David
• 金额: $ 6.85万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=748045
• 关键词: New; Molecules; Methods; Platforms; Interface

This proposal supports multidisciplinary training in organic chemistry; Our long-term vision is to devise new synthetic methods and synthesize new molecules to answer important questions and solve problems in chemistry and biology. Research is fundamental and addresses significant challenges in methodology, synthesis, molecular recognition, and catalysis with applications in fine-chemical synthesis, imaging, medicinal chemistry and the design of the next generation of "smart drugs" and sensors made of DNA. Our preliminary data and ongoing work and recent publications augur for success in these goals. Specifically, we will advance knowledge through the pursuit of five long-term goals not funded by other grants. 1.Synthesize bioactive natural products and peptides based on novel modified indoles: We will synthesize challenging compounds featuring new work on modified indoles (a natural heterocycle). These bring new synthetic know-how and new probes for key biological targets. 2.Develop late-stage fluorescent isoindole stapled peptide macrocycles: Based on our discovery of fluorescent isoindole peptide stapling, we will develop a powerful chemical platform to discover high-affinity peptides with emergent fluorescence to provide tools for cell-based screens and confocal studies. 3.Synthesize new RBF3s as isosteres for applications in biology: Organotrifluoroborates (RBF3s) are anions that mimic carboxylates in biology. Excitingly, RBF3s enable facile PET imaging, an application that we invented. We propose new methods for synthesizing new RBF3s that will be studied in biochemical assays. 4.Use Organofluoroborates for C-F Bond Formation: Fluorinated compounds are highly prized in agrichemicals, pharmaceuticals and materials but are difficult to prepare. Our interest in RBF3s led us to discover a new application where RBF3s can be used as cheap reagents to fluorinate carbon. Novel methods are proposed to exploit this. 5.Expand chemical functionality in DNAzymes & aptamers for sensing, imaging, and therapeutic leads: DNA is an exciting technological platform for selecting catalysts and ligands capable serving as "smart drugs" and sensors. Here we will merge chemical synthesis and molecular biology to evolve novel hybrid DNA catalysts that contain protein-like functionalities for enhanced specificity and activity. These projects represent new and risky ideas that have the high potential for breakthroughs that can be spun out for additional funding by agencies and industries that will fund highly applied projects based on more mature results. The multidisciplinary nature of this proposed research and the training it provides is unparalleled in Canada in terms of the breadth and depth. With a track record of publishing and training in these five above subjects, along with a record of leveraging and commercializing previous NSERC-funded work, we are uniquely qualified to execute on these goals.

该提案支持有机化学的多学科培训；我们的长期愿景是设计新的合成方法，合成新的分子，以回答化学和生物学中的重要问题和解决问题。研究是基础，解决了方法论、合成、分子识别和催化方面的重大挑战，并应用于精细化学合成、成像、药物化学以及下一代“智能药物”和DNA传感器的设计。我们的初步数据和正在进行的工作以及最近的出版物预示着这些目标的成功。具体来说，我们将通过追求五个没有得到其他资助的长期目标来推进知识。1.基于新型修饰吲哚合成具有生物活性的天然产物和多肽：我们将合成具有修饰吲哚（天然杂环）新工作的具有挑战性的化合物。这为关键的生物靶点带来了新的合成技术和新的探针。2.开发后期荧光异吲哚肽钉环：基于我们发现的荧光异吲哚肽钉环，我们将开发一个强大的化学平台来发现高亲和肽与紧急荧光，为基于细胞的筛选和共聚焦研究提供工具。3.有机三氟硼酸盐（RBF3s）是生物学中类似羧酸盐的阴离子。令人兴奋的是，rbf3可以实现PET成像，这是我们发明的一项应用。我们提出了新的方法来合成新的RBF3s，将在生化分析研究。4.使用有机氟硼酸盐形成C-F键：氟化化合物在农业化学品、药品和材料中非常珍贵，但很难制备。我们对RBF3s的兴趣使我们发现了一种新的应用，RBF3s可以用作廉价的氟化碳试剂。提出了利用这一特性的新方法。5.扩展DNAzymes和适配体的化学功能，用于传感、成像和治疗先导：DNA是一个令人兴奋的技术平台，可以选择催化剂和配体，作为“智能药物”和传感器。在这里，我们将结合化学合成和分子生物学来进化新的杂交DNA催化剂，它含有类似蛋白质的功能，以增强特异性和活性。这些项目代表了新的和有风险的想法，具有很高的突破潜力，可以由机构和行业提供额外的资金，这些机构和行业将根据更成熟的结果为高度应用的项目提供资金。这项拟议研究的多学科性质及其提供的培训在广度和深度方面在加拿大是无与伦比的。凭借在上述五个主题上的出版和培训的记录，以及利用和商业化以前nserc资助的工作的记录，我们有独特的资格来执行这些目标。