RAPID: Conserved Regions of the SARS-CoV-2 virus (COVID-19) RNA-RNA Interactions that Mediate Genome Dimerization and/or Progression Through the Viral Life Cycle

导致2019冠状病毒病（COVID-19）的病毒——严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）的基因组以RNA编码。该奖项资助博士的研究。杜肯大学的Mihaela-Rita Mihailescu和Jeffrey D. Evanseck致力于确定RNA中的结构和信号，这些结构和信号控制着病毒在其生命周期的各个阶段的进展。Drs。Mihailescu和Evanseck使用生物物理和计算方法来确定距离较远的RNA部分的结构如何相互作用，从而从早期蛋白质生产转向后期病毒生产。此外，该项目还研究了保守结构如何将两个分离的rna结合在一起，从而通过称为重组的过程在基因组之间交换部分。这一重组过程有助于了解SARS-CoV-2基因组是如何从感染不同哺乳动物物种的病毒rna之间的遗传物质交换中产生的。该项目对社会的影响是确定RNA-RNA相互作用的潜在抑制剂，从而进一步为开发针对SARS-CoV-2病毒的治疗性干预措施提供线索，并相应地阻止COVID-19大流行。本研究的目的是通过SARS-CoV-2生命周期的重要步骤阐明控制其进展的分子机制，并揭示一种新的、未被探索的RNA基因组二聚化机制，可能促进其重组。这项研究指导了未来针对SARS-CoV-2和其他类似RNA病毒基因组RNA的新抗病毒药物的开发。生物信息学和生物物理方法，包括荧光光谱，将被应用于阐明一个高度保守的s2m RNA基序的功能，并探测病毒基因的5 ' -和3 ' -非翻译区（utr）中保守序列之间的远程RNA-RNA相互作用。s2m RNA基序被提出形成一个“接吻复合体”中间体，介导SARS-CoV-2 RNA基因组的二聚化，从而促进冠状病毒和其他共享该基序的病毒家族中的重组事件。utr被提出形成“亲吻相互作用”，介导基因组循环，控制翻译和复制病毒生命周期步骤之间的过渡的分子开关。这笔拨款是使用《冠状病毒援助、救济和经济安全（关怀）法案》分配给MPS的补充资金提供的资金。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), the virus that causes coronavirus disease 2019 (COVID-19), is encoded in RNA. This award funds studies by Drs. Mihaela-Rita Mihailescu and Jeffrey D. Evanseck at Duquesne University in to determine the structures and signals in the RNA that control the progression of the virus through various stages of its life cycle. Drs. Mihailescu and Evanseck use biophysical and computational methods to determine how structures of distantly separated parts of the RNA interact to switch from early stage protein production to late stage virus production. In addition, the project studies how conserved structures bring two separate RNAs together to allow parts to swap between genomes through a process called recombination. This recombination process provides an understanding for how the SARS-CoV-2 genome may have arisen from the exchange of genetic material among RNAs from viruses that infect different mammalian species. The impact of the project on society is to identify potential inhibitors against RNA-RNA interactions, which further provides leads for the development of therapeutic interventions against the SARS-CoV-2 virus and, correspondingly, stem the COVID-19 pandemic.This goal of this study is to elucidate the molecular mechanisms controlling the progression of SARS-CoV-2 through essential steps of its life cycle and unravel a new, unexplored mechanism of RNA genomic dimerization that might facilitate its recombination. This research guides future development of new antivirals that target the genomic RNA of SARS-CoV-2 and potentially other similar RNA viruses. Bioinformatics and biophysical methods, including fluorescence spectroscopy, will be applied to elucidate the function of a highly conserved s2m RNA motif and to probe the long-range RNA-RNA interactions between the conserved sequences in the 5’- and 3’-untranslated regions (UTRs) of viral genes. The s2m RNA motif is proposed to form a “kissing complex” intermediate that mediates dimerization of the SARS-CoV-2 RNA genome, thereby facilitating recombination events in coronaviruses and other additional viral families that share this motif. The UTRs are proposed to form "kissing interactions" that mediate the genome circularization, molecular switch that controls the transition between the translation and replication viral life cycle steps.This grant is being awarded using funds made available by the Coronavirus Aid, Relief, and Economic Security (CARES) Act supplemental funds allocated to MPS.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.