Antiviral Drug Screen of Kinase Inhibitors Identifies Cellular Signaling Pathways Critical for SARS-CoV-2 Replication

Abstract

The emergence of a highly contagious novel coronavirus, SARS-CoV-2 that causes COVID-19, has precipitated the current global health crisis. However, our knowledge of the mechanisms of COVID-19 pathogenesis is very limited which has hampered attempts to develop targeted antiviral strategies. We developed a medium-throughput primary drug screening system and identified a small molecule library of 34 of 430 protein kinase inhibitors that were capable of inhibiting viral cytopathic effect in epithelial cells. These drug inhibitors are all in various stages of clinical trials. We detected key proteins involving in cellular signaling pathways mTOR-PI3K-AKT, ABL-BCR/MAPK, and DNA-Damage Response pathways that are critical for SARS-CoV-2 infection. A drug-protein interaction based secondary screen confirmed compounds such as Berzosertib (VE-822) and Nilotinib with anti SARS-CoV-2 activity, in which Berzosertib demonstrated potent antiviral activity in a human epithelial cell line and human induced pluripotent stem cell-derived cardiomyocytes. Our study highlights key promising kinase inhibitors to constrain SARS-CoV-2 replication as a host-directed therapy in the treatment of COVID-19 and provides an important mechanism of host-pathogen interactions.Funding: This research was funded by UCLA DGSOM and Broad Stem Cell Research Center institutional award (OCRC #20-1) to V.A. and California Institute for Regenerative Medicine Discovery Award (DISC2COVID19-11764) to B.G and (TRAN1COVID19-11975) to V.A., an institutional training grant (T32 HL116273) to A.S., and an American Heart Association Rapid Response Grant to A.S and C.N.S. Conflict of Interest: The authors declare no competing financial interests.Ethical Approval: This study was performed in strict accordance with the recommendations of UCLA.