P9R is a defensin-like peptide that exhibits potent antiviral activity against pH-dependent viruses, including the avian influenza A(H7N9) virus, coronaviruses (SARS-CoV-2, MERS-CoV and SARS-CoV), and the non-enveloped rhinovirus. The antiviral activity of P9R depends on direct binding to viruses and inhibition of virus-host endosomal acidification but when P9R was added to cells after SARS-CoV-2 infection, P9R could significantly inhibit viral replication. P9R can also protect mice in lethal challenge models.