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Mirror Image Aptamers: Next Generation RNA-Binding Reagents for Basic Research and Therapeutic Applications

镜像适体：用于基础研究和治疗应用的下一代 RNA 结合试剂

基本信息

批准号：
10240632
负责人：
Jonathan Thomas Sczepanski
金额：
$ 35.52万
依托单位：
TEXAS A&M UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2023-08-31
项目状态：
已结题

项目摘要

Project Summary/Abstract The increasing appreciation of RNA's structure-function relationship has led to a demand for new technologies that enable targeting of specific RNA structures. Such technologies are essential for the development of probes to study RNA function and therapeutics to treat RNA-mediated diseases. However, outside of antibiotics binding the ribosome, structure-specific RNA-binding reagents are very rare. Thus, developing of new technologies that enable structure-specific targeting of RNA remains an important challenge in many fields. The central vision of my research program is to address the deficit of structure-specific RNA-binding reagents using a radically different type of nucleic acid affinity reagent: L-aptamers. L-Aptamers are unique because they are comprised of L-(deoxy)ribose-based nucleic acids (L-DNA and L-RNA), which are mirror images (enantiomers) of natural D-nucleotides. Because oligonucleotides of opposite stereochemistry (D versus L) are incapable of forming contiguous Watson-Crick base pairs with each other, we are able to evolve L-aptamers that adaptively bind structured D-RNA targets through tertiary interactions (shape) rather than primary sequence. In other words, L-aptamers escape the tyranny of Watson-Crick base pairing, enabling a more nuanced mode of molecular recognition to be discovered. As a result, L-aptamers bind structured RNAs with greater affinity and specificity compared to conventional affinity reagent. Binding RNAs based on their shape rather than Watson-Crick base pairing represents a significant departure from traditional oligonucleotide-based approaches and represents a major advance in aptamer technology. During the next five year, my research group aims to further develop L-aptamer technology in order to realize its promise as a practical research and therapeutic tool. In particular, we will focus on incorporation of modified nucleotides that bestow protein-like functionality on L-aptamers, thus generating a novel class of RNA-targeted antibody mimetics. Because these technological developments will be carried out in the context of disease associated RNAs, such as oncogenic microRNAs and viral RNAs, this work will have an immediate impact by generating lead reagents to probe the etiology of disease and develop new therapeutic strategies. In line with my vision, we aim to determine the structure of an L-aptamer–D-RNA complex, which will provide insight into this novel mode of recognition and inform future L-aptamer design.

项目总结/摘要对RNA结构-功能关系的日益重视导致了对新的RNA的需求。这些技术能够靶向特定的RNA结构。这些技术对于开发研究RNA功能的探针和治疗RNA介导的疾病的疗法。然而，在这方面，除了结合核糖体的抗生素之外，结构特异性RNA结合试剂非常罕见。因此，在本发明中，开发新技术，使结构特异性靶向RNA仍然是一个重要的挑战在许多领域。我的研究计划的中心愿景是解决结构特异性RNA结合的缺陷使用完全不同类型的核酸亲和试剂的试剂：L-适体。L-适体是独一无二的因为它们由基于L-（脱氧）核糖的核酸（L-DNA和L-RNA）组成，它们是镜像的，天然D-核苷酸的图像（对映体）。因为具有相反立体化学的寡核苷酸（D 相对于L）不能形成连续的沃森-克里克碱基对彼此，我们能够进化通过三级相互作用（形状）而不是通过与结构化的D-RNA靶标自适应结合的L-适体主要序列换句话说，L-适体逃脱了沃森-克里克碱基配对的暴政，使其能够在细胞内进行。更微妙的分子识别模式有待发现。因此，L-适体结合结构化RNA 与常规亲和试剂相比具有更大的亲和性和特异性。结合RNA的基础上，形状而不是沃森-克里克碱基配对代表了与传统碱基配对的显著偏离。这是一种基于寡核苷酸的方法，代表了适体技术的重大进展。在接下来的五年里，我的研究小组的目标是进一步开发L-适体技术，实现其作为实用研究和治疗工具的承诺。特别是，我们将重点关注纳入修饰的核苷酸，其赋予L-适体蛋白质样功能，从而产生一类新的 RNA靶向抗体模拟物。因为这些技术发展将在疾病相关的RNA，如致癌microRNA和病毒RNA，这项工作将有一个直接的通过生产先导试剂来探测疾病的病因和开发新的治疗策略，在根据我的设想，我们的目标是确定L-适体-D-RNA复合物的结构，这将提供深入了解这种新识别模式并为未来的L-适体设计提供信息。