Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2
Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2
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DOI：
10.1038/s41421-020-0153-3
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发表时间：
2020-03-16
期刊：
影响因子：
33.5
通讯作者：
Cheng, Feixiong
中科院分区：
文献类型：
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作者：
Zhou, Yadi;Hou, Yuan;Cheng, Feixiong
人类冠状病毒(HCoV)包括严重急性呼吸综合征冠状病毒(SARS-CoV)和2019年新型冠状病毒(2019-nCoV，又称SARS-CoV-2)，以高发病率和高死亡率引领全球疫情。然而，目前还没有针对2019-nCoV/SARS-CoV-2的有效药物。药物再利用作为从现有药物中发现药物的一种有效策略，与从头发现药物相比，可以缩短时间，降低成本。在这项研究中，我们提出了一种综合的、抗病毒药物再利用的方法，实现了一个基于系统药理学的网络医学平台，量化了人类蛋白-蛋白质相互作用网络中HCoV-宿主相互作用组和药物靶标之间的相互作用。对15个HCoV全基因组的系统发育分析表明，2019-nCoV/SARS-CoV-2与SARS-CoV的核苷酸序列同源性最高(79.7%)。具体地说，2019-nCoV/SARS-CoV-2的囊膜蛋白和核衣壳蛋白是进化上保守的两个区域，与SARS-CoV的序列同源性分别为96%和89.6%。利用药物靶标的网络邻近分析和人类冠状病毒与宿主的相互作用，我们优先选择了16种潜在的抗HCoV可重复使用药物(例如褪黑素、硫代嘌呤和西罗莫斯)，这些药物通过对药物基因特征和HCoV诱导的人类细胞系转录数据的浓缩分析进一步得到验证。我们进一步确定了三种潜在的药物组合(例如，西罗莫司+放线菌素，硫代嘌呤+褪黑素，托瑞米芬+大黄素)：这些药物的靶点都击中了HCoV-宿主子网络，但目标是人类相互作用组网络中的单独社区。总之，这项研究为快速识别针对2019-nCoV/SARS-CoV-2的候选可重复使用药物和潜在的药物组合提供了强大的基于网络的方法。
Human coronaviruses (HCoVs), including severe acute respiratory syndrome coronavirus (SARS-CoV) and 2019 novel coronavirus (2019-nCoV, also known as SARS-CoV-2), lead global epidemics with high morbidity and mortality. However, there are currently no effective drugs targeting 2019-nCoV/SARS-CoV-2. Drug repurposing, representing as an effective drug discovery strategy from existing drugs, could shorten the time and reduce the cost compared to de novo drug discovery. In this study, we present an integrative, antiviral drug repurposing methodology implementing a systems pharmacology-based network medicine platform, quantifying the interplay between the HCoV-host interactome and drug targets in the human protein-protein interaction network. Phylogenetic analyses of 15 HCoV whole genomes reveal that 2019-nCoV/SARS-CoV-2 shares the highest nucleotide sequence identity with SARS-CoV (79.7%). Specifically, the envelope and nucleocapsid proteins of 2019-nCoV/SARS-CoV-2 are two evolutionarily conserved regions, having the sequence identities of 96% and 89.6%, respectively, compared to SARS-CoV. Using network proximity analyses of drug targets and HCoV-host interactions in the human interactome, we prioritize 16 potential anti-HCoV repurposable drugs (e.g., melatonin, mercaptopurine, and sirolimus) that are further validated by enrichment analyses of drug-gene signatures and HCoV-induced transcriptomics data in human cell lines. We further identify three potential drug combinations (e.g., sirolimus plus dactinomycin, mercaptopurine plus melatonin, and toremifene plus emodin) captured by the "Complementary Exposure" pattern: the targets of the drugs both hit the HCoV-host subnetwork, but target separate neighborhoods in the human interactome network. In summary, this study offers powerful network-based methodologies for rapid identification of candidate repurposable drugs and potential drug combinations targeting 2019-nCoV/SARS-CoV-2.