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

Author:

Manfredonia Ilaria1ORCID,Nithin Chandran2ORCID,Ponce-Salvatierra Almudena2ORCID,Ghosh Pritha2ORCID,Wirecki Tomasz K2ORCID,Marinus Tycho1ORCID,Ogando Natacha S3ORCID,Snijder Eric J3ORCID,van Hemert Martijn J3ORCID,Bujnicki Janusz M2ORCID,Incarnato Danny1ORCID

Affiliation:

1. Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute (GBB), University of Groningen, Nijenborgh 7, 9747 AG, Groningen, the Netherlands

2. Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology in Warsaw, ul. Ks. Trojdena 4, 02-109 Warsaw, Poland

3. Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, the Netherlands

Abstract

AbstractSARS-CoV-2 is a betacoronavirus with a linear single-stranded, positive-sense RNA genome, whose outbreak caused the 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 coronavirus structural RNA elements have been identified to date. Here, we performed RNA structure probing to obtain single-base resolution secondary structure maps of the full SARS-CoV-2 coronavirus genome both in vitro and in living infected cells. Probing data recapitulate the previously described coronavirus RNA elements (5′ UTR and s2m), and reveal new structures. Of these, ∼10.2% show significant covariation among SARS-CoV-2 and other coronaviruses, hinting at their functionally-conserved role. Secondary structure-restrained 3D modeling of these segments further allowed for the identification of putative druggable pockets. In addition, we identify a set of single-stranded segments in vivo, showing 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.

Funder

Nederlandse Organisatie voor Wetenschappelijk Onderzoek

National Science Centre

Foundation for Polish Science

Groningen Biomolecular Sciences and Biotechnology Institute

Leiden University Fund

Bontius Foundation

Publisher

Oxford University Press (OUP)

Subject

Genetics

Reference61 articles.

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