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 hinders therapy development. We use a SARS-CoV-2 infection system in permissible human cells to study signaling changes by phosphoproteomics. We identify viral protein phosphorylation and define phosphorylation-driven host cell signaling changes upon infection. Growth factor receptor (GFR) signaling and downstream pathways are activated. Drug-protein network analyses revealed GFR signaling as key pathways targetable by approved drugs. The inhibition of GFR downstream signaling by five compounds prevents 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 a central pathway essential for SARS-CoV-2 replication. It provides novel strategies for COVID-19 treatment.

SARS-CoV-2 感染正在全球迅速蔓延。治疗方法的快速发展至关重要。然而，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缺乏了解，阻碍了治疗的发展。我们在允许的人类细胞中使用 SARS-CoV-2 感染系统，通过磷酸化蛋白质组学研究信号传导变化。我们识别病毒蛋白磷酸化并定义感染时磷酸化驱动的宿主细胞信号传导变化。生长因子受体 (GFR) 信号传导和下游途径被激活。药物-蛋白质网络分析揭示 GFR 信号传导是已批准药物可靶向的关键途径。通过细胞病变效应、病毒 dsRNA 产生和病毒 RNA 释放到上清液中进行评估，五种化合物抑制 GFR 下游信号传导可阻止 SARS-CoV-2 在细胞中复制。这项研究描述了 SARS-CoV-2 感染时的宿主细胞信号转导事件，并揭示了 GFR 信号转导是 SARS-CoV-2 复制所必需的中心途径。它为 COVID-19 治疗提供了新策略。