Control of molecular shape for the recognition of nucleic acid secondary structures

控制分子形状以识别核酸二级结构

• 批准号: RGPIN-2022-03875
• 负责人: Petitjean, Anne
• 金额: $ 2.11万
• 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: 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=748046
• 关键词: Control; molecular; shape; recognition; nucleic

Guanine quadruplexes (G4s) are shapes of DNA and RNA which regulate critical events such as cell aging and death, and the production of proteins, in particular those responsible for the development and progression of cancers, infections and neurological disorders. We propose to create and study several families of agents capable of finding G4s in cells, signalling them by emitting light and/or acting on G4s in a controlled manner. The long-term therapeutic goals are to (i) generate `smart' drugs which can selectively act in diseases such as cancer, neurological disorders, viral and parasite infections, with limited effects on healthy tissues, and (ii) create `army knife platforms' capable of integrating many functions in one agent. For instance, we want to let the agents find the G4s, signal where they are, and make a `permanent' knot on the DNA in order to prevent diseases from evolving, all in one go. Such multimodal action will greatly facilitate optimizing the agents' action, and offer more effective and targeted medicine. The proposed research also addresses the lack of tools to advance the fundamental progress of the G4 field, with novel emissive species that can be tuned to the need of individual laboratories around the globe. All in all, the proposed work will benefit Canada and beyond by providing clinicians with innovative and selective potential therapies, as well as researchers with performant tools to advance their own laboratory exploration. The approach that is taken in this proposal by targeting G4s in DNA and RNA is important because many current drugs focus on inhibiting proteins, and therefore often lead to the emergence of resistance (through a slight change in protein composition), rendering drugs ineffective. Pharmaceuticals acting on nucleic acid structures, however, are much more difficult to counteract, and therefore such therapeutic agents are more likely to remain active. Similarly, traditional laboratory tools for G4 investigation have reached their limits as the field has progressed, and novel tools with higher performance and multiple functions are now needed. Developing the proposed new agents and tools will expose the highly qualified personnel (HQP) to a range of concepts, fields and techniques. They become proficient in handling complex data search engines, strategizing organic and coordination chemical syntheses. Mastering analytical tools for drug development and biological assays, and developing trouble-shooting skills and flexibility in achieving their scientific goals, give them a strong advantage in the pharma job market and beyond. In addition, the diverse nature of the work in this research program primes our HQP to communicate with a variety of audiences, thanks to a wide range of scientific collaborations, and opportunities for interactions with the general public and individual patients.

鸟嘌呤四链体（G4）是DNA和RNA的形状，其调节关键事件，如细胞衰老和死亡，以及蛋白质的产生，特别是那些负责癌症、感染和神经系统疾病的发展和进展的蛋白质。我们建议创建和研究几个能够在细胞中发现G4的试剂家族，通过发光和/或以受控方式作用于G4来向它们发出信号。长期的治疗目标是：（一）生产“智能”药物，能够有选择地对癌症、神经紊乱、病毒和寄生虫感染等疾病起作用，对健康组织的影响有限;（二）创造能够将多种功能整合在一种药剂中的“军刀平台”。例如，我们希望让代理人找到G4，发出它们所在位置的信号，并在DNA上形成一个“永久”结，以防止疾病的进化，所有这些都是一次性的。这种多模式作用将极大地促进优化药物的作用，并提供更有效和更有针对性的药物。拟议的研究还解决了缺乏工具来推进G4领域的基本进展的问题，新的发射物质可以根据地球仪的需要进行调整。总而言之，拟议的工作将有利于加拿大和其他国家，为临床医生提供创新和选择性的潜在疗法，以及为研究人员提供性能工具，以推进他们自己的实验室探索。 该提案中通过靶向DNA和RNA中的G4的方法很重要，因为目前许多药物专注于抑制蛋白质，因此经常导致耐药性的出现（通过蛋白质组成的轻微变化），使药物无效。然而，作用于核酸结构的药物更难以抵消，因此这样的治疗剂更可能保持活性。同样，随着该领域的发展，用于G4调查的传统实验室工具已经达到了极限，现在需要具有更高性能和多种功能的新型工具。开发拟议的新代理和工具将使高素质人员（HQP）接触到一系列概念、领域和技术。他们精通处理复杂的数据搜索引擎，制定有机和协调化学合成的战略。掌握用于药物开发和生物测定的分析工具，并培养解决问题的技能和实现科学目标的灵活性，使他们在制药就业市场及其他领域具有强大的优势。此外，这项研究计划中工作的多样性使我们的HQP能够与各种受众进行沟通，这要归功于广泛的科学合作以及与公众和个体患者互动的机会。