Disruption of the nucleocapsid-RNA condensation by punicalagin is a broad-spectrum antiviral approach.

The formation of liquid condensates by nucleocapsid (N) protein and viral RNA is a critical and highly conserved event in the life cycle of numerous viruses. Targeting this process emerges as a possible strategy to combat viral infections. Here, we discover that punicalagin, a natural compound derived from Punica granatum, exhibits potent pan-antiviral activity. Through a screening of 2799 compounds, we identified that punicalagin inhibits the formation of N-RNA condensations at nanomolar concentrations, resulting in significant inhibition of viral replication. The oral administration of punicalagin effectively dampens the viral load in tissues of mice infected with various viruses, such as SARS-CoV-2, vesicular stomatitis virus (VSV) and influenza A virus (IAV). Moreover, we show that punicalagin also blocks the virus-stimulated inflammation by targeting mitochondrial antiviral signaling protein (MAVS), thereby alleviating tissue damage and lethality in the infected animals. Thus, by reporting that punicalagin targets the conserved process across different viruses, our work suggests a new paradigm for developing antiviral therapies against both current and future viral threats.