We report the antiviral activity of 95 single compounds from the Medicines for Malaria Venture (MVV) and the Calibr ReFRAME drug libraries and 30 combinations with the orally bioactive RdRp inhibitor molnupiravir against SARSCoV2. We performed this standardized medium-throughput screening by using the physiologically relevant reconstituted human airway epithelia MucilAir model (Epithelix), facilitating both reproducibility of results and a clear distinction between antiviral and toxic effects of compounds.

We found that selected combinations have the potential to boost antiviral activity compared to single treatments while requiring lower dosages of single active compounds. These data indicate that viral polymerase inhibitor-based combinations with repurposed drugs targeting host cells are worthy of further consideration as potential treatment strategies not only against COVID-19 but also against the other main virus respiratory infections.