Abstract
A new coronavirus was recently discovered and named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Infection with SARS-CoV-2 in humans causes coronavirus disease2019 (COVID-19) and has been rapidly spreading around the globe1,2. SARS-CoV-2 shows some similarities to other coronaviruses; however, treatment options and an understanding of how SARS-CoV-2 infects cells are lacking. Here we identify the host cell pathways that are modulated by SARS-CoV-2 and show that inhibition of these pathways prevents viral replication in human cells. We established a human cell-culture model for infection with a clinical isolate of SARS-CoV-2. Using this cell-culture system, we determined the infection profile of SARS-CoV-2 by translatome3 and proteome proteomics at different times after infection. These analyses revealed that SARS-CoV-2 reshapes central cellular pathways such as translation, splicing, carbon metabolism, protein homeostasis (proteostasis) and nucleic acid metabolism. Small-molecule inhibitors that target these pathways prevented viral replication in cells. Our results reveal the cellular infection profile of SARS-CoV-2 and have enabled the identification of drugs that inhibit viral replication. We anticipate that our results will guide efforts to understand the molecular mechanisms that underlie the modulation of host cells after infection with SARS-CoV-2. Furthermore, our findings provide insights for the development of therapies for the treatment of COVID-19.
Highlights
There is no established therapy for the treatment of COVID-19
Identifying and testing potential drug candidates for the treatment of COVID-19 is of high priority
Only limited data have been obtained that describes the response of the host cell to infection with SARS-CoV-2, preventing a databased assessment of treatment options
Summary
Concentrations that are not toxic to human Caco-2 cells (Fig. 2e, f and Extended Data Fig. 2i, j). Addition of pladienolide B, a spliceosome inhibitor that targets the splicing factor SF3B117, prevented viral replication at concentrations that were not toxic to the human Caco-2 cells (Fig. 3d and Extended Data Fig. 5c), revealing that splicing is an essential pathway for SARS-CoV-2 replication and a potential therapeutic target. Analyses of the effects of SARS-CoV-2 infection on the host cell proteome revealed major readjustments in cellular function, of splicing, proteostasis and nucleotide biosynthesis. Compounds that modulate these pathways prevented SARS-CoV-2 replication in human cells
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