Abstract
IMPORTANCE: Porcine deltacoronavirus (PDCoV) is an emerging swine enteric coronavirus that threatens the pig industry and acts as a viral spillover, infecting other farm animals and potentially humans. The recent emergence of highly pathogenic PDCoV in South Korea, causing severe neonatal piglet mortality, underscores the urgent need for effective countermeasures to mitigate economic and public health risks. Thus, discovering new therapeutic methods through drug repurposing is crucial for controlling PDCoV. OBJECTIVE: This study investigated ivermectin (IVM) for its antiviral effect on PDCoV in vitro and explored its mechanism of action. METHODS: The antiviral effects and mechanism of action of IVM against PDCoV were evaluated using various virological assays. RESULTS: IVM markedly impaired the replication of PDCoV in a dose-dependent manner. Time-of-addition assays showed that the anti-PDCoV activity of IVM was most potent when administered before infection, simultaneously with infection, or immediately after infection. Further mode of action experiments revealed that IVM targeted the replication stage of PDCoV infection at post-entry steps. CONCLUSIONS AND RELEVANCE: Our results indicated that IVM interfered with PDCoV genome replication by impairing viral RNA synthesis. These findings suggest the potential of IVM for inhibiting PDCoV RNA polymerase and provide an invaluable therapeutic strategy to combat PDCoV infection with IVM, offering a viable alternative in the absence of commercial vaccines.