The Combination of Remdesivir and Ivermectin Exerts Highly Potent and Synergistic Antiviral Activity Against Murine Coronavirus and SARS-CoV-2 Infections

The COVID-19 pandemic highlighted the urgent need to develop effective and broad-spectrum antiviral therapies against coronaviruses. One strategy to address this concern is combination therapy using repurposed drugs against zoonotic viruses with pandemic potential. We previously demonstrated that the combination of remdesivir and ivermectin is highly potent and synergistic in inhibiting the replication of murine hepatitis virus, a surrogate model for SARS-CoV-2. Time-of-addition and time-of-removal assays were performed to determine the viral replication processes affected. The interactions between the drug combination, virus and host were investigated by proteomics and bulk RNA sequencing of MHV-infected H2.35 mouse liver epithelial cells. The combination (at their respective IC50 concentrations) drastically diminished the coronavirus titer by ~4log10 greater than the respective monotherapies. Based on proteomic and transcriptomic analyses, viral protein and RNA levels were significantly depressed upon combination treatment. While remdesivir exhibited considerable negative effects upon host RNA processes, ivermectin resulted in the upregulation of host protein processes (e.g. response to unfolded protein; protein insertion into ER membrane). Molecular pathways affected by the combination treatment were markedly distinct from the monotherapies, and indicated that ivermectin enhances remdesivir by modulating critical host processes to synergistically exert its inhibitory effect on the coronavirus replication cycle.