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Genome-wide mapping of therapeutically-relevant SARS-CoV-2 RNA structures

View ORCID ProfileIlaria Manfredonia, View ORCID ProfileChandran Nithin, View ORCID ProfileAlmudena Ponce-Salvatierra, View ORCID ProfilePritha Ghosh, View ORCID ProfileTomasz K. Wirecki, View ORCID ProfileTycho Marinus, View ORCID ProfileNatacha S. Ogando, View ORCID ProfileEric J. Snider, View ORCID ProfileMartijn J. van Hemert, View ORCID ProfileJanusz M. Bujnicki, View ORCID ProfileDanny Incarnato
doi: https://doi.org/10.1101/2020.06.15.151647
Ilaria Manfredonia
1Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute (GBB), University of Groningen, Nijenborgh 7, 9747 AG, Groningen, the Netherlands
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  • ORCID record for Ilaria Manfredonia
Chandran Nithin
2Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology, ul. Ks. Trojdena 4, 02-109 Warsaw, Poland
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Almudena Ponce-Salvatierra
2Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology, ul. Ks. Trojdena 4, 02-109 Warsaw, Poland
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Pritha Ghosh
2Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology, ul. Ks. Trojdena 4, 02-109 Warsaw, Poland
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Tomasz K. Wirecki
2Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology, ul. Ks. Trojdena 4, 02-109 Warsaw, Poland
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Tycho Marinus
1Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute (GBB), University of Groningen, Nijenborgh 7, 9747 AG, Groningen, the Netherlands
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Natacha S. Ogando
3Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, the Netherlands
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  • ORCID record for Natacha S. Ogando
Eric J. Snider
3Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, the Netherlands
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Martijn J. van Hemert
3Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, the Netherlands
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  • For correspondence: d.incarnato@rug.nl iamb@genesilico.pl m.j.van_hemert@lumc.nl
Janusz M. Bujnicki
2Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology, ul. Ks. Trojdena 4, 02-109 Warsaw, Poland
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  • For correspondence: d.incarnato@rug.nl iamb@genesilico.pl m.j.van_hemert@lumc.nl
Danny Incarnato
1Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute (GBB), University of Groningen, Nijenborgh 7, 9747 AG, Groningen, the Netherlands
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  • For correspondence: d.incarnato@rug.nl iamb@genesilico.pl m.j.van_hemert@lumc.nl
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Summary

SARS-CoV-2 is a betacoronavirus with a linear single-stranded, positive-sense RNA genome of ∼30 kb, whose outbreak caused the still ongoing COVID-19 pandemic. The ability of coronaviruses to rapidly evolve, adapt, and cross species barriers makes the development of effective and durable therapeutic strategies a challenging and urgent need. As for other RNA viruses, genomic RNA structures are expected to play crucial roles in several steps of the coronavirus replication cycle. Despite this, only a handful of functionally conserved structural elements within coronavirus RNA genomes have been identified to date.

Here, we performed RNA structure probing by SHAPE-MaP to obtain a single-base resolution secondary structure map of the full SARS-CoV-2 coronavirus genome. The SHAPE-MaP probing data recapitulate the previously described coronavirus RNA elements (5′ UTR, ribosomal frameshifting element, and 3′ UTR), and reveal new structures. Secondary structure-restrained 3D modeling of highly-structured regions across the SARS-CoV-2 genome allowed for the identification of several putative druggable pockets. Furthermore, ∼8% of the identified structure elements show significant covariation among SARS-CoV-2 and other coronaviruses, hinting at their functionally-conserved role. In addition, we identify a set of persistently single-stranded regions having high sequence conservation, suitable for the development of antisense oligonucleotide therapeutics.

Collectively, our work lays the foundation for the development of innovative RNA-targeted therapeutic strategies to fight SARS-related infections.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • http://www.incarnatolab.com/datasets/SARS_Manfredonia_2020.php

  • http://dx.doi.org/10.17632/8gj97c4kgv.1

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted June 15, 2020.
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Genome-wide mapping of therapeutically-relevant SARS-CoV-2 RNA structures
Ilaria Manfredonia, Chandran Nithin, Almudena Ponce-Salvatierra, Pritha Ghosh, Tomasz K. Wirecki, Tycho Marinus, Natacha S. Ogando, Eric J. Snider, Martijn J. van Hemert, Janusz M. Bujnicki, Danny Incarnato
bioRxiv 2020.06.15.151647; doi: https://doi.org/10.1101/2020.06.15.151647
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Genome-wide mapping of therapeutically-relevant SARS-CoV-2 RNA structures
Ilaria Manfredonia, Chandran Nithin, Almudena Ponce-Salvatierra, Pritha Ghosh, Tomasz K. Wirecki, Tycho Marinus, Natacha S. Ogando, Eric J. Snider, Martijn J. van Hemert, Janusz M. Bujnicki, Danny Incarnato
bioRxiv 2020.06.15.151647; doi: https://doi.org/10.1101/2020.06.15.151647

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