Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of
coronavirus disease 2019 (COVID-19), has emerged as a major global health threat. The
COVID-19 pandemic has resulted in over 168 million cases and 3.4 million deaths to date, while the number of cases continues to rise. With limited therapeutic options, the identification of safe and effective
therapeutics is urgently needed. The repurposing of known clinical compounds holds the potential for rapid identification of drugs effective against SARS-CoV-2. Here, we utilized a library of FDA-approved and well-studied preclinical and clinical compounds to screen for
antivirals against SARS-CoV-2 in human pulmonary epithelial cells. We identified 13 compounds that exhibit potent
antiviral activity across multiple orthogonal assays. Hits include known
antivirals, compounds with anti-inflammatory activity, and compounds targeting host pathways such as
kinases and
proteases critical for SARS-CoV-2 replication. We identified seven compounds not previously reported to have activity against SARS-CoV-2, including B02, a human RAD51 inhibitor. We further demonstrated that B02 exhibits synergy with
remdesivir, the only
antiviral approved by the FDA to treat
COVID-19, highlighting the potential for combination
therapy. Taken together, our comparative compound screening strategy highlights the potential of drug repurposing screens to identify novel starting points for development of effective
antiviral mono- or combination
therapies to treat
COVID-19.