Abstract
Effective antiviral drugs are essential to combat COVID-19 and future pandemics. Although many compounds show antiviral in vitro activity, only a few retain effectiveness in vivo against SARS-CoV-2. Here, we show that berbamine (Berb) is effective against SARS-CoV, MER-CoV, SARS-CoV-2 and its variants, including the XBB.1.16 variant. In hACE2.Tg mice, Berb suppresses SARS-CoV-2 replication through two distinct mechanisms: inhibiting spike-mediated viral entry and enhancing antiviral gene expression during infection. The administration of Berb, in combination with remdesivir (RDV), clofazimine (Clof) and fangchinoline (Fcn), nearly eliminated viral load and promoted recovery from acute SARS-CoV-2 infection and its variants. Co-housed mice in direct contact with either pre-treated or untreated infected mice exhibited negligible viral loads, reduced lung pathology, and decreased viral shedding, suggesting that Berb may effectively hinder virus transmission. This broad-spectrum activity positions Berb as a promising preventive or therapeutic option against betacoronaviruses.