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Related Concept Videos

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Antisense oligonucleotides targeting the SARS-CoV-2 nucleocapsid gene decrease viral titers in hamsters.

Christopher Fitzpatrick1,2, Nicolas Meunier2, Sophie Lepoder3

  • 1Université Paris-Saclay, AgroParisTech, INRAE, GABI UMR1313, 78350 Jouy-en-Josas, France.

Molecular Therapy. Nucleic Acids
|July 21, 2025
PubMed
Summary
This summary is machine-generated.

Antisense oligonucleotides (ASOs) targeting SARS-CoV-2 nucleocapsid RNA show promise as a novel antiviral strategy. ASO-N1 demonstrated significant efficacy in reducing viral load and improving clinical signs in infected hamsters.

Keywords:
COVID-19MT: OligonucleotidesRNA therapyTherapies and Applicationsantiviralmorpholinosnucleocapsidsynergistic effect

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Area of Science:

  • Virology and Molecular Biology
  • Antiviral Therapeutics
  • Oligonucleotide Therapeutics

Background:

  • Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes the ongoing COVID-19 pandemic.
  • Emerging SARS-CoV-2 variants and limited antiviral efficacy necessitate new therapeutic approaches.
  • Antisense oligonucleotides (ASOs) offer a potential strategy for targeting viral RNA.

Purpose of the Study:

  • To design, screen, and evaluate antisense oligonucleotides (ASOs) targeting SARS-CoV-2 genomic and sub-genomic RNA.
  • To identify and validate a lead ASO candidate for in vivo efficacy against SARS-CoV-2 infection.
  • To assess the conserved nature of the ASO target site across SARS-CoV-2 variants.

Main Methods:

  • Design and screening of ASOs targeting SARS-CoV-2 RNA using luminescence-based reporter assays and RT-qPCR in human cells.
  • In vivo validation in SARS-CoV-2 infected hamsters treated with intranasal and systemic ASO-N1.
  • Evaluation of clinical signs, viral RNA levels, cytokine expression, and infectious viral titers.
  • Sequence analysis to assess target site conservation across SARS-CoV-2 variants.

Main Results:

  • ASO-N1, targeting nucleocapsid RNA, was selected as the lead candidate.
  • ASO-N1 treatment in hamsters significantly improved clinical signs, reduced weight loss, and increased food consumption.
  • Sustained reduction in viral RNA and inflammatory cytokines in nasal mucosa, and decreased infectious viral titers observed.
  • Optimized ASO-N1 chemistry synergistically enhanced in vitro antiviral efficacy.
  • The ASO-N1 target site is conserved across major SARS-CoV-2 variants over four years.

Conclusions:

  • Nucleocapsid RNA-targeting antisense oligonucleotides represent a promising and robust antiviral strategy against SARS-CoV-2.
  • ASO-N1 demonstrates significant in vivo efficacy and potential for broad applicability against SARS-CoV-2 variants.