Synthesis and Applications of Chemically-Modified Oligonucleotides

核酸是DNA和RNA的主要组成部分，它们是具有巨大生物功能的生物大分子。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。自从65年前发现DNA的双螺旋结构以来，在核酸领域取得了重大进展，以改善其在生物技术或现代医学中的应用。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，我的研究项目开发合成类似物，以*改善其生物功能。然后，我的研究小组评估了这些*合成类似物的生物学影响。*我的研究小组的主要重点是合成新型的*化学修饰的寡核苷酸用作基因沉默寡核苷酸。*首先，我们将探索在一类称为短干扰RNA(SiRNAs)的基因沉默分子中展开小分子的效果。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，我们将扩大能够直接与不同细胞生物成分相互作用的分子的范围和位置。当结合时，这些分子可能会表现出更好的效力、细胞膜通透性和稳定性。*其次，我们将扩大siRNA中光响应基团的范围。我们的实验室已经证明，当将光响应分子偶氮苯置于siRNAs的核心中心区时，可以*用来可逆地控制基因沉默活动的时间。偶氮苯分别在可见光和紫外光存在下，可以在反式和顺式之间异构化。我们将扩大光响应*RNA基团的范围，并探索siRNA中功能化的偶氮苯衍生物。这将使我们能够微调siRNAs的活性，并使我们能够更好地控制其活性，从而防止*脱靶效应。最后，我的研究小组在开发*寡核苷酸的新型骨架修饰方面拥有专业知识。我们将扩大这些修改的范围，并探索它们在CRISPR(集群规则间隔*短回文重复)/Cas9编辑系统中的影响。CRISPR/CAS9系统是一个令人兴奋的相对较新的系统，已被证明在各种生物系统中都是可接受的。*多学科*实验室工作由一支由本科生和研究生组成的才华横溢的团队进行，他们结合使用了溶液相、固相和生物*技术。因此，从我的实验室指导的实习生为各种职业做好了充分的准备，包括专注于化学和科学的职业。

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.