A SARS-CoV-2 protein interaction map reveals targets for drug repurposing
A SARS-CoV-2 protein interaction map reveals targets for drug repurposing
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DOI：
10.1038/s41586-020-2286-9
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发表时间：
2020-04-30
期刊：
影响因子：
64.8
通讯作者：
Krogan, Nevan J.
中科院分区：
文献类型：
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作者：
Gordon, David E.;Jang, Gwendolyn M.;Krogan, Nevan J.
一张人类与SARS-CoV-2蛋白质相互作用图突出显示了被病毒劫持的细胞过程，这些过程可以被现有药物靶向，包括mRNA翻译抑制剂和预测的sigma受体调节剂。（SARS-CoV-2），这是2019年冠状病毒病的病原体（COVID-19）已感染超过230万人，导致超过16万人死亡，并造成全球社会和经济混乱（1，2）。目前还没有经临床证实有效的抗病毒药物用于治疗COVID-19，也没有任何疫苗可以预防SARS-CoV-2感染，由于对SARS-CoV-2如何感染细胞的分子细节了解有限，开发药物和疫苗的努力受到阻碍。在这里，我们克隆，标记和表达的26个29 SARS-CoV-2蛋白在人类细胞中，并确定了人类蛋白质的物理相关的每一个SARS-CoV-2蛋白质使用亲和纯化质谱，确定了332高置信蛋白质之间的相互作用SARS-CoV-2和人类蛋白质。其中，我们确定了69种化合物靶向的66种可药用人类蛋白质或宿主因子（其中29种药物已获得美国食品和药物管理局批准，12种药物正在临床试验中，28种药物为临床前化合物）。我们在多种病毒检测中筛选了其中的一个子集，发现了两组显示抗病毒活性的药理学药物：mRNA翻译抑制剂和预测的sigma-1和sigma-2受体调节剂。对这些宿主因子靶向药物的进一步研究，包括它们与直接靶向病毒酶的药物的组合，可能会导致治疗COVID-19的治疗方案。
A human-SARS-CoV-2 protein interaction map highlights cellular processes that are hijacked by the virus and that can be targeted by existing drugs, including inhibitors of mRNA translation and predicted regulators of the sigma receptors.A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption(1,2). There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein-protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors. Further studies of these host-factor-targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.