Abstract
SummarySARS-CoV-2 has currently precipitated the COVID-19 global health crisis. We developed a medium-throughput drug-screening system and identified a small-molecule library of 34 of 430 protein kinase inhibitors that were capable of inhibiting the SARS-CoV-2 cytopathic effect in human epithelial cells. These drug inhibitors are in various stages of clinical trials. We detected key proteins involved in cellular signaling pathways mTOR-PI3K-AKT, ABL-BCR/MAPK, and DNA-damage response that are critical for SARS-CoV-2 infection. A drug-protein interaction-based secondary screen confirmed compounds, such as the ATR kinase inhibitor berzosertib and torin2 with anti-SARS-CoV-2 activity. Berzosertib exhibited potent antiviral activity against SARS-CoV-2 in multiple cell types and blocked replication at the post-entry step. Berzosertib inhibited replication of SARS-CoV-1 and the Middle East respiratory syndrome coronavirus (MERS-CoV) as well. Our study highlights key promising kinase inhibitors to constrain coronavirus replication as a host-directed therapy in the treatment of COVID-19 and beyond as well as provides an important mechanism of host-pathogen interactions.
Highlights
The current pandemic is caused by a newly discovered coronavirus, severe-acute-respiratory-syndrome-related coronavirus 2 (SARS-CoV-2)
COVID-19 is a multi-organ disease affecting lung, heart, kidney, and brain (Hou et al, 2020; Xu et al, 2020b, Dolhnikoff et al, 2020; Fanelli et al, 2020; Puelles et al, 2020; Lu et al, 2020; Paterson et al, 2020). This virus enters into a host cell by binding its transmembrane spike glycoprotein (S protein) to the cellular membrane angiotensin-converting enzyme 2 (ACE2) receptor, which is expressed in various organs (Kai and Kai, 2020)
The SARS-CoV-2 isolate USA-WA1/2020 was obtained from BEI Resources of the National Institute of Allergy and Infectious Diseases (NIAID), and studies involving live virus were conducted in a biosafety level 3 (BSL3) high-containment facility
Summary
The current pandemic is caused by a newly discovered coronavirus, severe-acute-respiratory-syndrome-related coronavirus 2 (SARS-CoV-2). COVID-19 is a multi-organ disease affecting lung, heart, kidney, and brain (Hou et al, 2020; Xu et al, 2020b, Dolhnikoff et al, 2020; Fanelli et al, 2020; Puelles et al, 2020; Lu et al, 2020; Paterson et al, 2020) This virus enters into a host cell by binding its transmembrane spike glycoprotein (S protein) to the cellular membrane angiotensin-converting enzyme 2 (ACE2) receptor, which is expressed in various organs (Kai and Kai, 2020). This results from viral replication in epithelial cells causing cell injury, a vigorous inflammation-dominated response, organ failure, and possibly, death
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