Korea VirusResearch Institute

Amid growing global concerns over the resurgence of COVID-19 and the emergence of new variants, a research team led by Director Young Ki Choi at the IBS Korea Virus Research Institute has developed a novel antiviral candidate that blocks the formation of the virus’s RNA replication complex. Unlike existing drugs that directly inhibit the complex’s activity, this new approach prevents the complex from forming by disrupting the interaction between key viral proteins, particularly at the conserved NSP12-NSP8 binding site.

The team designed four structure-based peptides that selectively bind to NSP12 and block NSP8, thereby inhibiting viral RNA replication. The peptides showed strong antiviral effects in both cell experiments and mouse models, offering full protection even with intranasal administration. The treatment was effective both before and after infection.

This study highlights a promising universal antiviral strategy and the potential of peptide-based therapeutics for respiratory viruses. The results were published in Molecular Therapy (IF 12.9) on May 27.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication depends on the NSP12-NSP8-NSP7 complex, which plays a critical role in enhancing RNA-dependent RNA polymerase (RdRp) activity. NSP8 is particularly essential, stabilizing the RdRp complex and supporting viral replication across diverse variants. To disrupt this crucial interaction, we designed four NSP8-derived peptides-N8-Pepα, N8-Pepα_cyc, N8-Pepβ, and N8-PepβD-targeting a key hotspot region within the NSP12-NSP8 interface that governs complex stability and processivity. In vitro assays demonstrated that these peptides effectively inhibit RdRp activity by disrupting the NSP12-NSP8 interaction, leading to significant reductions in SARS-CoV-2 replication in Vero E6 cells. Notably, intranasal administration of N8-Pepα or N8-Pepα_cyc (25 mg/kg) in Balb/c mice provided robust antiviral protection, alleviating weight loss and reducing mortality following challenge with a mouse-adapted SARS-CoV-2 strain. Both prophylactic and therapeutic treatments significantly lowered viral titers and minimized pathological damage in the nasal turbinates and lungs. These results highlight the NSP12-NSP8 interface as a novel and highly conserved target for antiviral therapy and establish NSP8-derived peptides, particularly N8-Pepα and N8-Pepα_cyc, as promising candidates for inhibiting RdRp complex formation and controlling SARS-CoV-2 replication.