Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic, resulting millions of infections and deaths with few effective interventions available. Here, we demonstrate that SARS-CoV-2 evades interferon (IFN) activation in respiratory epithelial cells, resulting in a delayed response in bystander cells. Since pretreatment with IFNs can block viral infection, we reasoned that pharmacological activation of innate immune pathways could control SARS-CoV-2 infection. To identify potent antiviral innate immune agonists, we screened a panel of 75 microbial ligands that activate diverse signaling pathways and identified cyclic dinucleotides (CDNs), canonical STING agonists, as antiviral. Since CDNs have poor bioavailability, we tested the small molecule STING agonist diABZI, and found that it potently inhibits SARS-CoV-2 infection of diverse strains including variants of concern (B.1.351) by transiently stimulating IFN signaling. Importantly, diABZI restricts viral replication in primary human bronchial epithelial cells and in mice in vivo. Our study provides evidence that activation of STING may represent a promising therapeutic strategy to control SARS-CoV-2.

严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 已引起全球大流行，导致数百万人感染和死亡，但几乎没有有效的干预措施。在这里，我们证明 SARS-CoV-2 可以逃避呼吸道上皮细胞中干扰素 (IFN) 的激活，从而导致旁观者细胞的反应延迟。由于干扰素预处理可以阻止病毒感染，我们推断先天免疫途径的药理学激活可以控制 SARS-CoV-2 感染。为了鉴定有效的抗病毒先天免疫激动剂，我们筛选了一组 75 种微生物配体，这些配体可激活不同的信号通路，并鉴定出环状二核苷酸 (CDN)（典型的 STING 激动剂）具有抗病毒作用。由于 CDN 的生物利用度较差，我们测试了小分子 STING 激动剂 diABZI，发现它通过瞬时刺激 IFN 信号传导，有效抑制包括关注变体 (B.1.351) 在内的多种病毒株的 SARS-CoV-2 感染。重要的是，diABZI 限制原代人支气管上皮细胞和小鼠体内的病毒复制。我们的研究提供的证据表明，STING 的激活可能是控制 SARS-CoV-2 的一种有前途的治疗策略。