Alisporivir inhibits MERS- and SARS-coronavirus replication in cell culture, but not SARS-coronavirus infection in a mouse model

•In cell culture models, low-micromolar doses of alisporivir block SARS-CoV and MERS-CoV replication.•Combination treatment with alisporivir and ribavirin increases the anti-MERS-CoV activity in cell culture.•Combination treatment with alisporivir and ribavirin does not protect against SARS-CoV infection in a mouse model.•Cyclophilin-binding drugs should be explored further in the context of host-directed anti-coronaviral strategies.

Currently, there is no registered treatment for infections with emerging zoonotic coronaviruses like SARS- and MERS-coronavirus. We here report that in cultured cells low-micromolar concentrations of alisporivir, a non-immunosuppressive cyclosporin A-analog, inhibit the replication of four different coronaviruses, including MERS- and SARS-coronavirus. Ribavirin was found to further potentiate the antiviral effect of alisporivir in these cell culture-based infection models, but this combination treatment was unable to improve the outcome of SARS-CoV infection in a mouse model. Nevertheless, our data provide a basis to further explore the potential of Cyp inhibitors as host-directed, broad-spectrum inhibitors of coronavirus replication.