Viruses with Single-Stranded, Positive-Sense RNA Genomes

Modrow, Susanne; Falke, D.; Truyen, Uwe; Schätzl, Hermann

doi:10.1007/978-3-642-20718-1_14

Cited by 42 publications

(38 citation statements)

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“…However, RNA motifs within positive-strand RNA viruses guide many processes that are critical for the virus life cycle (You et al 2004;McMullan et al 2007;Friebe and Bartenschlager 2009;Modrow et al 2013;Pirakitikulr et al 2016). SARS-CoV-2 is unlikely to be an exception to this rule, particularly given that, to our knowledge, it has the most elaborately structured RNA genome that has ever been reported to date, and many of its constituent structures are conserved across coronavirus families (Chen and Olsthoorn 2010;Madhugiri et al 2018;Rangan et al 2020).…”

Section: Discussionmentioning

confidence: 99%

The global and local distribution of RNA structure throughout the SARS-CoV-2 genome

Tavares

Mahadeshwar

Pyle

2020

Preprint

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AbstractSARS-CoV-2 is the causative viral agent of COVID-19, the disease at the center of the current global pandemic. While knowledge of highly structured regions is integral for mechanistic insights into the viral infection cycle, very little is known about the location and folding stability of functional elements within the massive, ~30kb SARS-CoV-2 RNA genome. In this study, we analyze the folding stability of this RNA genome relative to the structural landscape of other well-known viral RNAs. We present an in-silico pipeline to locate regions of high base pair content across this long genome and also identify well-defined RNA structures, a method that allows for direct comparisons of RNA structural complexity within the several domains in SARS-CoV-2 genome. We report that the SARS-CoV-2 genomic propensity to stable RNA folding is exceptional among RNA viruses, superseding even that of HCV, one of the most highly structured viral RNAs in nature. Furthermore, our analysis reveals varying levels of RNA structure across genomic functional regions, with accessory and structural ORFs containing the highest structural density in the viral genome. Finally, we take a step further to examine how individual RNA structures formed by these ORFs are affected by the differences in genomic and subgenomic contexts. The conclusions reported in this study provide a foundation for structure-function hypotheses in SARS-CoV-2 biology, and in turn, may guide the 3D structural characterization of potential RNA drug targets for COVID-19 therapeutics.

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Section: Discussionmentioning

confidence: 99%

The global and local distribution of RNA structure throughout the SARS-CoV-2 genome

Tavares

Mahadeshwar

Pyle

2020

Preprint

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“…The members of the Coronaviridae family are viruses with positive-sense singlestranded RNA genomes (1). At present, some members of this family, such as SARS, MERS, and SARS-CoV-2 represent pathogens of great concern to public health.…”

Section: Introductionmentioning

confidence: 99%

Vitamin B12 May Inhibit RNA-Dependent-RNA Polymerase Activity of nsp12 from the SARS-CoV-2 Virus

Narayanan

Nair

2020

Preprint

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SARS-CoV-2 is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. Like other members of this family, the virus possesses a positive-sense single-stranded RNA genome. The genome encodes for the nsp12 protein, which houses the RNA-dependent-RNA polymerase (RdRP) activity responsible for the replication of the viral genome. A homology model of nsp12 was prepared using the structure of the SARS nsp12 (6NUR) as a model. The model was used to carry out in silico screening to identify molecules among natural products, or FDA approved drugs that can potentially inhibit the activity of nsp12. This exercise showed that vitamin B12 (methylcobalamin) may bind to the active site of the nsp12 protein. A model of the nsp12 in complex with substrate RNA and incoming NTP showed that Vitamin B12 binding site overlaps with that of the incoming nucleotide. A comparison of the calculated energies of binding for RNA plus NTP and methylcobalamin suggested that the vitamin may bind to the active site of nsp12 with significant affinity. It is, therefore, possible that methylcobalamin binding may prevent association with RNA and NTP and thus inhibit the RdRP activity of nsp12. Overall, our computational studies suggest that methylcobalamin form of vitamin B12 may serve as an effective inhibitor of the nsp12 protein. A. MeCo RNA GTP B. MeCo RNA MeCo GTP Figure 5: Binding site of methylcobalamin (MeCo) overlaps with that of incoming nucleotide. (A) Superimposition of the models of the functional ternary complex (cyan) and that of SCV2-nsp12:methylcobalamin (green) is displayed. The protein chains are shown in ribbon representation. The catalytic residues (cyan), incoming GTP (red) and methylcobalamin (magenta) are shown in stick representation and the cofactor ions are shown as spheres (B)The surface of the protein molecule is displayed and the RNA, incoming nucleotide, and methylcobalamin are shown in stick representation and coloured white, red and magenta, respectively. The vitamin B12 binding site overlaps with that of the incoming nucleotide and the terminal primer nucleotide.

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“…The members of the Coronaviridae family are viruses with positive-sense single-stranded RNA genomes. 1 At present, some members of this family, such as SARS, MERS, and SARS-CoV-2 represent pathogens of great concern to public health. SARS-CoV-2 is responsible for the ongoing pandemic of COVID-19, which started in the city of Wuhan in China, has now spread to more than 200 countries.…”

Section: Introductionmentioning

confidence: 99%

Vitamin B12 may inhibit RNA‐dependent‐RNA polymerase activity of nsp12 from the SARS‐CoV‐2 virus

Narayanan

Nair

2020

IUBMB Life

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SARS‐CoV‐2 is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. Like other members of this family, the virus possesses a positive‐sense single‐stranded RNA genome. The genome encodes for the nsp12 protein, which houses the RNA‐dependent‐RNA polymerase (RdRP) activity responsible for the replication of the viral genome. A homology model of nsp12 was prepared using the structure of the SARS nsp12 (6NUR) as a model. The model was used to carry out in silico screening to identify molecules among natural products, or Food and Drug Administration‐approved drugs that can potentially inhibit the activity of nsp12. This exercise showed that vitamin B12 (methylcobalamin) may bind to the active site of the nsp12 protein. A model of the nsp12 in complex with substrate RNA and incoming NTP showed that vitamin B12 binding site overlaps with that of the incoming nucleotide. A comparison of the calculated energies of binding for RNA plus NTP and methylcobalamin suggested that the vitamin may bind to the active site of nsp12 with significant affinity. It is, therefore, possible that methylcobalamin binding may prevent association with RNA and NTP and thus inhibit the RdRP activity of nsp12. Overall, our computational studies suggest that methylcobalamin form of vitamin B12 may serve as an effective inhibitor of the nsp12 protein.

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Viruses with Single-Stranded, Positive-Sense RNA Genomes

Cited by 42 publications

References 1 publication

The global and local distribution of RNA structure throughout the SARS-CoV-2 genome

The global and local distribution of RNA structure throughout the SARS-CoV-2 genome

Vitamin B12 May Inhibit RNA-Dependent-RNA Polymerase Activity of nsp12 from the SARS-CoV-2 Virus

Vitamin B12 may inhibit RNA‐dependent‐RNA polymerase activity of nsp12 from the SARS‐CoV‐2 virus

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