SARS-CoV-2 infections are rapidly spreading around the globe. The rapid development of therapies is of major importance. However, our lack of understanding of the molecular processes and host cell signaling events underlying SARS-CoV-2 infection hinder therapy development. We employed a SARS-CoV-2 infection system in permissible human cells to study signaling changes by phospho-proteomics. We identified viral protein phosphorylation and defined phosphorylation-driven host cell signaling changes upon infection. Growth factor receptor (GFR) signaling and downstream pathways were activated. Drug-protein network analyses revealed GFR signaling as key pathway targetable by approved drugs. Inhibition of GFR downstream signaling by five compounds prevented SARS-CoV-2 replication in cells, assessed by cytopathic effect, viral dsRNA production, and viral RNA release into the supernatant. This study describes host cell signaling events upon SARS-CoV-2 infection and reveals GFR signaling as central pathway essential for SARS-CoV-2 replication. It provides with novel strategies for COVID-19 treatment.

中文翻译：

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生长因子受体信号传导抑制阻止SARS-CoV-2复制

SARS-CoV-2感染正在全球范围内迅速传播。疗法的迅速发展是至关重要的。但是，我们对SARS-CoV-2感染背后的分子过程和宿主细胞信号转导事件的了解不足，阻碍了治疗的发展。我们在允许的人类细胞中采用了SARS-CoV-2感染系统来研究磷酸化蛋白质组学的信号变化。我们确定了病毒蛋白的磷酸化，并定义了感染后磷酸化驱动的宿主细胞信号传导的变化。生长因子受体（GFR）信号和下游通路被激活。药物-蛋白质网络分析表明，GFR信号传导是批准药物可靶向的关键途径。通过细胞病变效应，病毒dsRNA产生来评估，五种化合物对GFR下游信号的抑制作用阻止了SARS-CoV-2在细胞中的复制，病毒RNA释放到上清液中。这项研究描述了SARS-CoV-2感染后的宿主细胞信号转导事件，并揭示了GFR信号转导是SARS-CoV-2复制必不可少的中心途径。它提供了COVID-19治疗的新策略。