As global concerns grow regarding the possibility of a resurgence of the novel coronavirus disease (COVID-19) and the emergence of various variant viruses, domestic researchers have proposed a new treatment strategy that surpasses the limitations of existing antiviral agents.
The research team led by Choi Young-ki, director of the Institute for Basic Science (IBS) Korean Virus Research Institute, announced on the 23rd that they developed a new antiviral candidate substance that blocks the formation of the ribonucleic acid (RNA) replication enzyme complex, which is key to the proliferation of the COVID-19 virus, and proved its efficacy. This research achievement was published in the prestigious journal of cell and gene therapy, Molecular Therapy, on May 27.
The COVID-19 virus (SARS-CoV-2) utilizes the 'RNA-dependent RNA polymerase (RdRp) complex' to replicate itself. This replication enzyme complex helps replicate the viral genetic material, allowing for the creation of new viruses, and it operates by interlocking three proteins: NSP12, NSP8, and NSP7. Among these, NSP8 plays a critical role by stabilizing the overall structure.
Currently widely used antiviral agents such as remdesivir and molnupiravir directly inhibit the activity of this complex, but their effectiveness against variant viruses is limited and there is a risk of resistance. Therefore, the researchers attempted a new approach different from existing antiviral agents; instead of blocking the operation of the complex, they aimed to prevent the formation of the complex by blocking the interactions between the proteins.
To achieve this, the researchers focused on the binding site between NSP12 and NSP8. This site is a well-conserved region across various COVID-19 variant viruses and is characterized by being less affected by mutations. After precisely analyzing this binding site using cryo-electron microscopy, the researchers developed four types of peptides that mimic the structure.
Furthermore, they optimized the structure so that the peptides could act stably in the body and introduced cell-penetrating sequences to allow them to pass through cell membranes. The developed peptide-based antiviral agents selectively bind to NSP12 and block the approach of NSP8, preventing the complex from forming normally. As a result, they inhibit viral RNA replication and proliferation.
The researchers validated the antiviral effects of these peptides through cell experiments and mouse infection models. The experimental results showed that the peptides inhibited RNA replication of the COVID-19 virus, reducing the viral load in infected cells and tissues. In particular, administering them through the nostrils of mice resulted in a 100% survival rate against lethal infections, significantly reduced weight loss and lung damage, demonstrating a strong preventive and therapeutic effect. Additionally, efficacy was observed regardless of the timing of administration before or after infection.
Director Choi Young-ki noted, "The binding site targeted by this research is highly conserved among various COVID-19 variant viruses," and added, "This approach targeting it has the potential to develop into a universal antiviral strategy that can respond to the emergence of new variant viruses."
The research team plans to enhance the stability of the peptides and optimize the delivery system to increase the feasibility of clinical applications.
References
Molecular Therapy (2025), DOI: https://doi.org/10.1016/j.ymthe.2025.05.028