A Virucidal And Endosomal Trapping Peptide Against Human Adenoviruses In Respiratory Organoids And Hamsters

Human adenoviruses (HAdVs) are common respiratory pathogens that cause severe, life-threatening infections in immunocompromised individuals and children. Despite their medical importance, no clinically approved antiviral drugs exist. Here, we showed that 4H30, a 4-branched human defensin peptide, exhibited broad-spectrum antiviral activity against multiple HAdV subtypes in A549 and Calu-3 cells with negligible cytotoxicity and a high barrier to viral resistance in A549 cells. Mechanistic studies demonstrated that 4H30 exhibited a unique dual mechanism of action: direct virucidal activity through capsid disruption and endosomal trapping by impairing protein VI-mediated membrane penetration. Notably, 4H30 remained effective against HAdV-3 in human respiratory organoids and against HAdV-2 and HAdV-5 in an immunosuppressed hamster model, significantly reducing viral replication and disease-associated pathology. These findings demonstrate that 4H30 can inhibit multiple HAdVs through a novel mechanism, offering a new therapeutic avenue against HAdV infections.