RAPID: Measuring RNA Tertiary Contacts in SARS-CoV2

导致2019冠状病毒病（COVID-19）的严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）病毒的基因组被编码为RNA。该奖项资助俄勒冈州尤金市俄勒冈大学的Victoria J. DeRose博士研究病毒RNA的三维结构。德罗斯博士使用铂类化合物与RNA碱基化学结合，以确定RNA不同部分之间的距离。将距离信息与计算机预测相结合，可以得到SARS-CoV-2 RNA基因组的图像。该项目对社会的影响是确定病毒基因组中的潜在靶点，这为开发针对COVID-19大流行的治疗干预措施提供了进一步的线索。该项目的结果可能会通过提供准确建模其RNA结构所需的信息，影响理解和开发针对SARS-CoV2的治疗方法的能力。本项目开发的方法可能适用于下一个突发病毒。重要的是，该项目将支持博士生进行将化学生物学应用于基础科学的研究，并立即应用于重大的全球危机。该项目的目标是通过化学交联测量三级接触，实现SARS-CoV2 RNA结构的三维建模。使用铂（II）交联试剂获得SARS-CoV2 RNA结构域内和之间RNA-RNA相互作用的文库。由此产生的远程连接图提供了距离限制，以补充计算和核磁共振光谱研究，用于推导病毒rna的三维模型。将这些模型与溶液和哺乳动物细胞中的RNA进行比较，有助于加快对病毒功能至关重要的RNA过程的小分子靶向。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The genome of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus that causes coronavirus disease 2019 (COVID-19) is encoded in RNA. This award funds studies by Dr. Victoria J. DeRose at the University of Oregon in Eugene, OR to characterize the three-dimensional structure of the viral RNA. Dr. DeRose uses platinum compounds that chemically attach to RNA bases to determine distances separating different parts of the RNA. Combining the distance information with computer predictions leads to a picture of the SARS-CoV-2 RNA genome. The impact of the project on society is to identify potential target sites in the viral genome, which provides further leads for the development of therapeutic interventions against the COVID-19 pandemic.Results from this project may impact the ability to understand and develop therapeutics targeting SARS-CoV2 by providing information required to accurately model its RNA structures. Methods developed in this project may be applicable to the next emergent virus. Importantly, this project will support PhD students in research that applies chemical biology to fundamental science with immediate application to a major global crisis.The goal of this project is to enable three-dimensional modeling of SARS-CoV2 RNA structures by measuring tertiary contacts through chemical crosslinking. Platinum (II) crosslinking reagents are used to obtain a library of RNA-RNA interactions in and between SARS-CoV2 RNA domains. The resulting long-range connectivity maps provide distance constraints to complement computational and NMR spectroscopic studies for the derivation of three-dimensional models of the viral RNAs. These models are compared to the RNA in solution and in mammalian cells, helping to expedite small molecule targeting of RNA processes that are critical to virus function.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.