Development of a highly stable, active small interfering RNA with broad activity against SARS-CoV viruses

Area of Science:

• Molecular Biology
• Virology
• Drug Discovery

Background:

• Limited therapeutic options exist for COVID-19, necessitating novel antiviral strategies.
• SARS-CoV-2 variants, such as Omicron BA.2, exhibit resistance to existing treatments like antibodies.

Purpose of the Study:

• To optimize a nuclease-resistant siRNA targeting a conserved region of SARS-CoV-2 for broad antiviral activity.
• To evaluate the efficacy of the optimized siRNA against emerging SARS-CoV-2 variants.
• To explore the use of a second siRNA as a rescue molecule to prevent viral escape mutations.

Main Methods:

• Design and chemical modification of siRNA targeting the SARS-CoV-2 leader region.
• Assessment of siRNA nuclease resistance and in vitro antiviral activity.
• Testing siRNA efficacy against the SARS-CoV-2 Omicron BA.2 sublineage.

Main Results:

• Modified siRNA demonstrated nuclease resistance without compromising antiviral activity.
• The optimized siRNA effectively inhibited SARS-CoV-2, including the Omicron BA.2 variant.
• A secondary siRNA targeting the 5'-UTR showed potential as a rescue molecule to mitigate resistance.

Conclusions:

• Nuclease-resistant siRNA targeting conserved SARS-CoV-2 regions represents a promising therapeutic candidate.
• This siRNA-based strategy offers potential for broad-spectrum treatment against current and future SARS-CoV-2 variants.