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Antisense oligonucleotides targeting ORF1b block replication of severe acute respiratory syndrome coronavirus 2

Sophie Dhorne-Pollet1, Christopher Fitzpatrick1,2, Bruno Da Costa3

  • 1INRAE, AgroParisTech, GABI, Université Paris-Saclay, Jouy-en-Josas, France.

Frontiers in Microbiology
|November 17, 2022
PubMed

Insights

Antisense oligonucleotides targeting the SARS-CoV-2 genome show promise for COVID-19 treatment. An anti-ORF1b oligonucleotide significantly reduced viral replication in cell models, demonstrating potential for new therapies.

Area of Science:

  • Virology
  • Molecular Biology
  • Therapeutics

Background:

  • The COVID-19 pandemic necessitates novel therapeutic interventions.
  • Antisense oligonucleotide (ASO) technology offers a potential strategy for targeting viral genomes.

Purpose of the Study:

  • To investigate the efficacy of antisense oligonucleotides (ASOs) against the SARS-CoV-2 genome.
  • To identify specific ASOs that can inhibit viral replication in vitro.

Main Methods:

  • In silico prediction of four ASO gapmers targeting SARS-CoV-2 regions (ORF1a, ORF1b, N, 5'UTR).
  • Transfection of ASOs into human ACE2-expressing HEK-293T and monkey VeroE6/TMPRSS2 cells infected with SARS-CoV-2.
  • Quantification of viral genome copies and titration to assess viral replication.

Main Results:

  • The ASO targeting the ORF1b region demonstrated the highest efficiency, reducing viral genome copies by 71%.
  • ASOs targeting the N and 5'UTR regions also significantly reduced viral replication by 55% and 63%, respectively.
  • A significant decrease in SARS-CoV-2 multiplication was observed in both cell culture media and within cells.

Conclusions:

  • Antisense oligonucleotide technology, particularly targeting the ORF1b region, is a viable strategy for reducing SARS-CoV-2 replication in vitro.
  • This study provides proof-of-concept for ASOs as a promising therapeutic approach for COVID-19.
Keywords:
ASORNA therapyRNA virusSARS-CoV-2SARS-CoV-2 antisense therapy RNA viruscoronavirusoligonucleotide antisense therapy

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