Targeting viral suppressor of RNAi confers anti-coronaviral activity

Area of Science:

• Virology
• Molecular Biology
• Drug Discovery

Background:

• Coronaviruses pose significant global health threats, driving the need for novel antiviral therapies.
• RNA interference (RNAi) is a natural defense mechanism against viruses in mammals.
• Viruses often encode viral suppressors of RNAi (VSRs) to evade this defense, presenting VSRs as therapeutic targets.

Purpose of the Study:

• To design and evaluate peptides targeting the SARS-CoV-2 VSR, specifically the nucleocapsid (N) protein.
• To assess the potential of VSR-targeting peptides as a broad-spectrum antiviral strategy.

Main Methods:

• Design of peptides targeting the SARS-CoV-2 N protein.
• In vitro assessment of peptide interaction with N protein and its VSR activity.
• Evaluation of peptide efficacy against SARS-CoV-2 replication and variants.
• Testing against other human and animal coronaviruses.
• In vivo validation of antiviral activity.

Main Results:

• A peptide, designated GL, was identified that directly binds and inactivates the N protein's VSR activity.
• GL treatment restored RNAi response and significantly inhibited SARS-CoV-2 replication.
• GL demonstrated efficacy against multiple SARS-CoV-2 variants (Delta, Omicron BA.5, XBB, JN.1) and other coronaviruses (HCoV-229E, HCoV-OC43, MHV).
• In vivo studies confirmed the anti-coronaviral activity of GL.

Conclusions:

• The VSR-targeting peptide GL shows promise as a broad-spectrum anti-coronaviral therapeutic.
• Targeting viral suppressors of RNAi is a viable strategy for developing novel antiviral treatments.
• GL's broad efficacy highlights the potential of RNAi-based therapies against diverse viral threats.