Synthesis and Applications of Chemically-Modified Oligonucleotides

化学修饰寡核苷酸的合成及应用

• 批准号: RGPIN-2019-04692
• 负责人: Desaulniers, JeanPaul
• 金额: $ 2.11万
• 依托单位: University of Ontario Institute of Technology
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=714597
• 关键词: Synthesis; Applications; Chemically; Modified; Oligonucleotides

Nucleic acids are the main building blocks of DNA and RNA, which are biomacromolecules with vast biological function. For example, nucleic acids contain the genetic blue print of the cell, and transfer of this genetic code to messenger RNA is necessary to direct the synthesis of unique proteins. Nucleic acids also have other biological functions including controlling the expression of particular genes. Since the discovery of the double helical structure of DNA 65 years ago, there have been significant advances in the nucleic acid field to improve its properties for biotechnological applications or for modern medicine. For instance, gene-silencing oligonucleotides are tools used to understand gene function. However, limitations continue due to the native structure of these molecules. Using organic chemistry, my research program develops synthetic analogs in order to improve its biological function. My research group then evaluates the biological impact of these synthetic analogs. The primary focus of my research group involves synthesizing novel chemically-modified oligonucleotides to use as gene-silencing oligonucleotides. First, we will explore the effect of expanding small molecules within a class of gene silencing molecules called short interfering RNAs (siRNAs). My lab has identified an area within siRNAs that is amenable to diverse chemical modification. As such, we will expand the scope and place molecules that can interact directly with different cellular biological components. When bound, these molecules may exhibit improved potency, cell-membrane permeability, and stability. Secondly, we will expand the scope of photoresponsive groups within siRNAs. Our lab has shown that the photoresponsive molecule, azobenzene, when placed within the core central region of siRNAs can be used to reversibly control the timing of gene silencing activity. Azobenzene can isomerize between a trans and cis form in the presence of visible and ultra-violet light, respectively. We will expand the scope of photoresponsive RNA groups, and explore functionalized azobenzene derivatives within siRNAs. This will allow us to fine-tune the activity of siRNAs, and allow us to better control its activity, and thus prevent off-target effects. Finally, my research group has expertise in developing novel backbone modifications for oligonucleotides. We will expand the scope of these modifications and explore their effect within the CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 editing system. The CRISPR/Cas9 system is an exciting, and relatively new system that has been shown to be amenable within a variety of biological systems. The multidisciplinary laboratory work is conducted by a talented team of undergraduate and graduate students who use a combination of solution-phase, solid-phase and biological techniques. As such, the trainees supervised from my lab are well prepared for a variety of professions including careers focused in chemistry and science.

原子核 酸是DNA和RNA的主要组成部分，它们是生物大分子 具有巨大的生物功能。例如，核酸包含细胞的遗传蓝图，而将这种遗传密码转移到信使RNA是指导合成独特蛋白质所必需的。核酸还具有其他生物功能，包括控制特定基因的表达。自.以来 发现DNA的双螺旋结构65年前，已经有了 核酸领域的重大进展，以改善其性质 生物技术应用或现代医学。例如，基因沉默寡核苷酸是用于了解基因功能的工具。然而，由于这些分子的固有结构，限制仍然存在。利用有机化学，我的研究项目按顺序开发合成类似物 以提高其生物学功能。然后，我的研究小组评估了这些生物的影响 人工合成的类似物。 我的研究小组的主要工作重点是合成小说 用作基因沉默寡核苷酸的化学修饰的寡核苷酸。 首先，我们将探索在一个类内展开小分子的效果 称为短干扰RNA(SiRNAs)的基因沉默分子。我的实验室已经确定了siRNA中的一个区域，它可以进行不同的化学修饰。因此，我们将扩大范围和地点 可以直接与不同的细胞生物成分相互作用的分子。当结合时，这些分子可能表现出更好的效力、细胞膜通透性和稳定性。 第二， 我们将扩大siRNAs中光反应基团的范围。我们的实验室已经表明，光响应性 分子偶氮苯，当放置在siRNAs的核心中心区时，可以 用于可逆地控制基因沉默活动的时间。偶氮苯可以在反式和反式之间异构化 顺式化合物分别在可见光和紫外光存在下形成。我们将扩大光响应的范围 RNA基团，并探索siRNA中功能化的偶氮苯衍生物。这将允许我们微调活动 并使我们能够更好地控制其活动，从而防止 偏离目标的效果。 最后，我的 研究小组在开发新的主干修改方面具有专业知识 寡核苷酸。我们将扩大 这些修改的范围并探讨其在CRISPR内的影响(成组规则间隔 短回文重复)/Cas9编辑系统。这个 CRISPR/CAS9系统是一个令人兴奋的、相对较新的系统，它已经 被证明在各种生物系统中都是顺从的。 多学科的 实验室工作由本科生和研究生组成的才华横溢的团队进行。 将溶液相、固相和生物相结合使用的学生 技巧。因此，受训人员 在我实验室的监督下，为各种职业做好了充分的准备，包括 他的职业集中在化学和科学领域。