Zhou Yadi, Hou Yuan, Shen Jiayu, Huang Yin, Martin William, Cheng Feixiong
1Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195 USA.
2Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195 USA.
Cell Discov. 2020 Mar 16;6:14. doi: 10.1038/s41421-020-0153-3. eCollection 2020.
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 "" 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.
人类冠状病毒（HCoVs），包括严重急性呼吸综合征冠状病毒（SARS-CoV）和2019新型冠状病毒（2019-nCoV，也称为SARS-CoV-2），引发了全球范围内高发病率和高死亡率的疫情。然而，目前尚无针对2019-nCoV/SARS-CoV-2的有效药物。药物再利用作为一种从现有药物中发现有效药物的策略，与从头研发药物相比，可以缩短时间并降低成本。在本研究中，我们提出了一种综合的抗病毒药物再利用方法，该方法实施了一个基于系统药理学的网络医学平台，量化了人类蛋白质-蛋白质相互作用网络中HCoV-宿主相互作用组与药物靶点之间的相互作用。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的核苷酸序列同一性最高（79.7%）。具体而言，2019-nCoV/SARS-CoV-2的包膜蛋白和核衣壳蛋白是两个进化上保守的区域，与SARS-CoV相比，其序列同一性分别为96%和89.6%。通过对人类相互作用组中药物靶点和HCoV-宿主相互作用进行网络邻近性分析，我们对16种潜在的可用于抗HCoV的再利用药物（如褪黑素、巯嘌呤和西罗莫司）进行了优先级排序，这些药物通过药物-基因特征富集分析和人类细胞系中HCoV诱导的转录组学数据进一步得到验证。我们进一步确定了三种潜在的药物组合（如西罗莫司加放线菌素、巯嘌呤加褪黑素以及托瑞米芬加大黄素），它们被“ ”模式捕获：这些药物的靶点均作用于HCoV-宿主子网，但在人类相互作用组网络中靶向不同的邻域。总之，本研究提供了强大的基于网络的方法，用于快速鉴定针对2019-nCoV/SARS-CoV-2的候选再利用药物和潜在药物组合。
