SARS-CoV-2-RNA: Understanding the RNA architecture of SARS-CoV-2

SARS-CoV-2 RNA：了解 SARS-CoV-2 的 RNA 结构

• 批准号: 495006306
• 负责人: Professor Dr. Harald Schwalbe
• 金额: --
• 依托单位: Institut für Organische Chemie und Chemische Biologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/495006306?language=en
• 关键词: SARS; CoV; RNA; Understanding; architecture

The ongoing COVID-19 pandemic caused by the rapid and almost unmitigated spread of SARS-CoV-2 (SCoV-2) across the world necessitates the coordinated investigation of its viral proteins and RNAs to enable the rapid development of antiviral drugs. We use NMR-based structural biology to investigate structured elements found throughout the genomic RNA of SCoV-2 and in particular in its 5’- and 3’-untranslated regions (UTRs). Current biochemical RNA structure probing tools so far used on the SCoV-2 RNA are intrinsically unable to define the structural and dynamic features of the non-canonical bulge and loop regions of the structured RNA-elements in the SCoV-2 genome but revealed (i) that the structural elements in the genomic RNA are organized in a modular fashion with local structured elements connected by single-stranded regions, (ii) that they are conserved between related coronaviruses and thus their structure is of biological significance. Based on these findings, we propose a ‘divide-and-conquer’ approach where NMR-spectroscopy in solution can provide high-resolution information about their structure and dynamics. Our project is divided into three different objectives. Objective 1 is focussed on the detailed characterization of non-canonical RNA elements. The RNA structure and dynamics of these elements typically deviates from standard RNA structure and primes these elements to function as interaction hubs with other RNAs, proteins and potential inhibitors of viral propagation. Objective 2 focusses on the key replication element 5_SL5 in SCoV-2. We aim to determine the structure and dynamics of individual elements within 5_SL5 as well as reconstruct the entire RNA architecture by a combination of NMR and SAXS approaches. In Objective 3, we will focus on the investigation of structural and dynamic features of the -1 frameshift region in SCoV-2.

由于SARS-CoV-2病毒(SCOV-2)在世界各地的快速传播几乎有增无减，目前正在进行的新冠肺炎大流行要求对其病毒蛋白质和RNA进行协调研究，以实现抗病毒药物的快速开发。我们使用基于核磁共振的结构生物学来研究分布在SCOV-2基因组RNA中的结构元件，特别是在其5‘和3’非翻译区(UTRs)。到目前为止，用于SCOV-2 RNA的生化RNA结构探测工具本质上无法确定SCOV-2基因组中结构化RNA元件的非规范凸起和环区的结构和动态特征，但揭示了(1)基因组RNA中的结构元件是以模块化的方式组织的，局部结构元件由单链区连接；(2)它们在相关冠状病毒之间是保守的，因此它们的结构具有生物学意义。基于这些发现，我们提出了一种分而治之的方法，其中溶液中的核磁共振光谱可以提供关于它们的结构和动力学的高分辨率信息。我们的项目分为三个不同的目标。目标1集中在非规范RNA元件的详细特征上。这些元件的RNA结构和动力学通常偏离标准的RNA结构，并启动这些元件作为与其他RNA、蛋白质和潜在的病毒传播抑制因子的相互作用中心。目的2重点研究SCOV-2中的关键复制元件5_SL5。我们的目标是确定5_SL5中单个元件的结构和动力学，并结合核磁共振和SAXS方法重建整个RNA结构。在目标3中，我们将重点研究SCOV-2中-1移码区域的结构和动力学特征。