Synergistic antiviral activity of peptide inhibitors and a mutagenic base analog against SARS-CoV-2 proofreading and replication complexes

We explored a dual approach combining disruption of the viral replication complex with lethal mutagenesis to interfere with SARS-CoV-2 replication. We designed short inhibitory peptides that target the viral proofreading and RNA-capping machinery. In parallel, the mutagenic analog was evaluated to determine its effect on SARS-CoV-2 in Vero E6 cells. Next-generation sequencing revealed that dual treatment increased mutation frequency, altered mutant spectra, and decreased genome stability, consistent with progression toward error catastrophe. These findings reveal a dual antiviral mechanism that couples structure-guided peptide disruption of the SARS-CoV-2 replication complex with lethal mutagenesis, demonstrating a synergistic interaction between these two complementary processes.