The global epidemic caused by the coronavirus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in the infection of over 200 million people. To extend the knowledge of interactions between SARS-CoV-2 and humans, we systematically investigate the interactome of 29 viral proteins in human cells by using an antibody-based TurboID assay. In total, 1,388 high-confidence human proximal proteins with biotinylated sites are identified. Notably, we find that SARS-CoV-2 manipulates the antiviral and immune responses. We validate that the membrane protein ITGB1 associates angiotensin-converting enzyme 2 (ACE2) to mediate SARS-CoV-2 entry. Moreover, we reveal that SARS-CoV-2 proteins inhibit activation of the interferon pathway through the mitochondrial protein mitochondrial antiviral-signaling protein (MAVS) and the methyltransferase SET domain containing 2, histone lysine methyltransferase (SETD2). We propose 111 potential drugs for the clinical treatment of coronavirus disease 2019 (COVID-19) and identify three compounds that significantly inhibit the replication of SARS-CoV-2. The proximity labeling map of SARS-CoV-2 and humans provides a resource for elucidating the mechanisms of viral infection and developing drugs for COVID-19 treatment.

由冠状病毒严重急性呼吸系统综合症冠状病毒-2 (SARS-CoV-2) 引起的全球流行病已导致超过 2 亿人感染。为了扩展 SARS-CoV-2 与人类之间相互作用的知识，我们使用基于抗体的 TurboID 测定系统地研究了人类细胞中 29 种病毒蛋白的相互作用组。总共鉴定了 1,388 个具有生物素化位点的高可信度人类近端蛋白。值得注意的是，我们发现 SARS-CoV-2 可以操纵抗病毒和免疫反应。我们验证了膜蛋白 ITGB1 与血管紧张素转换酶 2 (ACE2) 相关联以介导 SARS-CoV-2 进入。而且，我们发现 SARS-CoV-2 蛋白通过线粒体蛋白线粒体抗病毒信号蛋白 (MAVS) 和含有 2，组蛋白赖氨酸甲基转移酶 (SETD2) 的甲基转移酶 SET 结构域抑制干扰素通路的激活。我们提出了 111 种可用于临床治疗 2019 年冠状病毒病 (COVID-19) 的潜在药物，并确定了三种可显着抑制 SARS-CoV-2 复制的化合物。SARS-CoV-2 与人类的邻近标记图为阐明病毒感染机制和开发 COVID-19 治疗药物提供了资源。