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

鸟嘌呤四链(G4S)是DNA和RNA的形状，调节细胞衰老和死亡等关键事件以及蛋白质的产生，特别是那些与癌症、感染和神经疾病的发生和发展有关的蛋白质。我们建议创建和研究几个能够在细胞中发现G4S的试剂家族，通过发光向G4S发出信号和/或以受控的方式作用于G4S。长期的治疗目标是：(1)生产可选择性地治疗癌症、神经疾病、病毒和寄生虫感染等疾病的“智能”药物，对健康组织影响有限；(2)创造能够在一种药剂中集成多种功能的“军刀平台”。例如，我们希望让代理人找到G4S，发出它们所在的信号，并在DNA上打一个永久的结，以防止疾病演变，所有这些都是一气呵成的。这种多模式的行动将极大地促进优化代理人的行动，并提供更有效和更有针对性的药物。这项拟议的研究还解决了缺乏工具来推动G4领域取得根本性进展的问题，提出了可以根据全球各个实验室的需要进行调整的新型发射物种。总而言之，这项拟议的工作将为加拿大和其他地区的临床医生提供创新和选择性的潜在疗法，并为研究人员提供性能良好的工具，以推进他们自己的实验室探索。在这项提案中，通过靶向DNA和RNA中的G4S而采取的方法很重要，因为许多当前的药物侧重于抑制蛋白质，因此经常导致耐药性的出现(通过蛋白质组成的轻微变化)，从而使药物无效。然而，作用于核酸结构的药物更难中和，因此这种治疗剂更有可能保持活性。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功能的新工具。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，制定有机和配位化学合成的战略。掌握药物开发和生物分析的分析工具，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和其他领域具有强大的优势。此外，由于广泛的科学合作以及与普通公众和个别患者互动的机会，这项研究计划中工作的多样性使我们的HQP能够与不同的受众进行交流。

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.