RAPID: Measuring RNA Tertiary Contacts in SARS-CoV2

引起2019冠状病毒病（COVID-19）的严重急性呼吸道综合征冠状病毒2（SARS-CoV-2）病毒的基因组由RNA编码。该奖项资助尤金的俄勒冈州大学的维多利亚J. DeRose博士的研究，以表征病毒RNA的三维结构。DeRose博士使用铂化合物化学附着在RNA碱基上，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，得出了SARS-CoV-2 RNA基因组的图片。该项目对社会的影响是确定病毒基因组中的潜在靶位点，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-CoV 2的治疗方法的能力。本项目开发的方法可能适用于下一次出现的病毒。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并立即应用于重大全球危机的研究。该项目的目标是通过化学交联测量三级接触来实现SARS-CoV 2 RNA结构的三维建模。铂（II）交联试剂用于获得SARS-CoV 2 RNA结构域中和之间的RNA-RNA相互作用的文库。由此产生的长程连接图提供了距离限制，以补充计算和NMR光谱研究的病毒RNA的三维模型的推导。这些模型与溶液和哺乳动物细胞中的RNA进行了比较，有助于加快RNA过程的小分子靶向，这对病毒功能至关重要。该奖项反映了NSF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.