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

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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.