Screening a Library of FDA-Approved and Bioactive Compounds for Antiviral Activity against SARS-CoV-2.
Scott B BieringErik Van DisEddie WehriLivia H YamashiroXammy NguyenlaClaire Dugast-DarzacqThomas G W GrahamJulien R StroumzaGuillaume R GolovkineAllison W RobertsDaniel M FinesJessica N SpradlinCarl C WardTeena BajajDustin DovalaUrsula Schulze-GamenRuchika BajajDouglas M FoxMelanie OttNiren MurthyDaniel K NomuraJulia SchaletzkySarah A StanleyPublished in: ACS infectious diseases (2021)
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.
Keyphrases
- sars cov
- respiratory syndrome coronavirus
- coronavirus disease
- combination therapy
- endothelial cells
- high throughput
- public health
- emergency department
- drug delivery
- small molecule
- stem cells
- induced pluripotent stem cells
- genome wide
- gene expression
- cancer therapy
- dna repair
- dna methylation
- pluripotent stem cells
- single cell
- sensitive detection
- bone marrow
- bioinformatics analysis