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

Area of Science:

• Virology
• RNA Biology
• Structural Biology
• Antiviral Therapeutics

Background:

• SARS-CoV-2, a betacoronavirus, causes the COVID-19 pandemic.
• Effective antiviral strategies are urgently needed due to rapid viral evolution.
• Genomic RNA structures are critical for coronavirus replication, but few conserved elements are known.

Purpose of the Study:

• To generate high-resolution secondary structure maps of the full SARS-CoV-2 genome.
• To identify functionally conserved RNA structures and potential therapeutic targets.
• To explore RNA-targeted therapeutic strategies against SARS-related infections.

Main Methods:

• RNA structure probing was performed in vitro and in infected cells to map genome-wide secondary structures.
• Covariation analysis was used to identify functionally conserved RNA elements across coronaviruses.
• Secondary structure-restrained 3D modeling was employed to identify druggable pockets.

Main Results:

• Single-base resolution secondary structure maps of the SARS-CoV-2 genome were generated.
• Previously known elements (5' UTR, s2m) were recapitulated, and novel structures were discovered.
• Approximately 10.2% of identified structures showed significant covariation, suggesting functional conservation.
• Putative druggable pockets were identified through 3D modeling of conserved RNA segments.
• Single-stranded, highly conserved segments suitable for antisense oligonucleotide therapeutics were identified in vivo.

Conclusions:

• This study provides comprehensive RNA secondary structure maps of the SARS-CoV-2 genome.
• Identified conserved RNA structures and druggable pockets offer new avenues for antiviral drug development.
• The findings support the development of innovative RNA-targeted therapeutics against SARS-CoV-2 and related viruses.