Repurposing Drugs and Synergistic Combinations as Potential Therapies for Inhibiting SARS-CoV‑2 and Coronavirus Replication

Drug repurposing can serve an important role in rapidly discovering medicament options for emerging microbial pandemics. In this study, a pragmatic approach is demonstrated for screening and testing drug combinations as potential broad-spectrum therapies against SARS-CoV-2 and other betacoronaviruses. Rapid cell-based phenotypic small molecule screens were executed using related common-cold-causing HCoV-OC43 betacoronavirus to identify replication inhibitors from a library of drugs approved by regulatory agencies for other indications. Given the best inhibitors, an expedient checkerboard strategy then served to identify synergistic drug combinations. These combinations were then validated using more challenging assays involving SARS-CoV-2 and variants. Promising drug combinations against multiple viral variants were discovered and involved Tilorone with Nelfinavir or Molnupiravir.