针对多种病毒利用的宿主因子进行靶向干预可能提供广谱的疫情应对解决方案。我们在对4,413个化合物进行SARS-CoV-2抑制剂筛选中发现了17个不同功能的候选物。我们证明了拉帕替尼和其他ErbB家族受体酪氨酸激酶抑制剂可以抑制SARS-CoV-2、委内瑞拉马脑炎病毒(VEEV)和其他高抗药性的新兴病毒的复制。拉帕替尼抑制了SARS-CoV-2的进入和后期病毒生命周期，并与直接抗病毒药物尼曼替韦尔显示出协同作用。我们发现ErbB1、2和4与SARS-CoV-2 S1蛋白结合，并调节病毒及ACE2的内化，它们对VEEV感染是必需的。在人类肺器官样结构中，拉帕替尼可以保护免受SARS-CoV-2诱导的ErbB调节的途径激活，这些途径与非感染性肺损伤、促炎细胞因子产生和上皮屏障损伤有关。拉帕替尼可以抑制VEEV的复制、细胞因子产生和微流控基础的人类神经血管单位的血脑屏障完整性破坏，并在致命感染小鼠模型中降低死亡率。我们验证了拉帕替尼介导的ErbB活性抑制作为抗病毒作用的重要机制。这些研究结果揭示了ErbBs通过调控病毒复制、炎症和组织损伤的方式，为抗击新兴病毒的再利用、ErbB靶向方法的原理提供了初步证明。

Targeting host factors exploited by multiple viruses could offer broad-spectrum solutions for pandemic preparedness. Seventeen candidates targeting diverse functions emerged in a screen of 4,413 compounds for SARS-CoV-2 inhibitors. We demonstrated that lapatinib and other approved inhibitors of the ErbB family receptor tyrosine kinases suppress replication of SARS-CoV-2, Venezuelan equine encephalitis virus (VEEV), and other emerging viruses with a high barrier to resistance. Lapatinib suppressed SARS-CoV-2 entry and later stages of the viral life cycle and showed synergistic effect with the direct-acting antiviral nirmatrelvir. We discovered that ErbB1, 2 and 4 bind SARS-CoV-2 S1 protein and regulate viral and ACE2 internalization, and they are required for VEEV infection. In human lung organoids, lapatinib protected from SARS-CoV-2-induced activation of ErbB-regulated pathways implicated in non-infectious lung injury, pro-inflammatory cytokine production, and epithelial barrier injury. Lapatinib suppressed VEEV replication, cytokine production and disruption of the blood-brain barrier integrity in microfluidic-based human neurovascular units, and reduced mortality in a lethal infection murine model. We validated lapatinib-mediated inhibition of ErbB activity as an important mechanism of antiviral action. These findings reveal regulation of viral replication, inflammation, and tissue injury via ErbBs and establish a proof-of-principle for a repurposed, ErbB-targeted approach to combat emerging viruses.