Matrix metallopeptidase 9 as a host protein target of chloroquine and melatonin for immunoregulation in COVID-19: A network-based meta-analysis
Matrix metallopeptidase 9 as a host protein target of chloroquine and melatonin for immunoregulation in COVID-19: A network-based meta-analysis
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DOI：
10.1016/j.lfs.2020.118096
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发表时间：
2020-09-15
期刊：
影响因子：
6.1
通讯作者：
Chakrabarti, Nilkanta
中科院分区：
文献类型：
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作者：
Hazra, Suvojit;Chaudhuri, Alok Ghosh;Chakrabarti, Nilkanta
目的：COVID-19的分子发病机制与其他冠状病毒（CoV）感染，即严重急性呼吸综合征（SARS）在人类中相似。由于缺乏合适的治疗策略，本研究旨在探索新型冠状病毒（COVID-19）的有效靶向药物对宿主蛋白的作用。材料和方法：从SARS-CoV患者血液微阵列数据库中筛选差异表达基因（DEG）。用于治疗COVID-19的重新用途药物选自现有文献。利用DEG和药物，构建了蛋白质-蛋白质相互作用（PPI）和化学-蛋白质相互作用（CPI）网络，并将其结合起来，建立了PPI-CPI网络的相互作用组模型。排名靠前的子网络及其枢纽瓶颈节点进行了评估与他们的功能annotations.Key结果：共识别出120个DEG和65种药物。PPI-CPI网络（118个节点和293条边）显示出一个顶级子网络（35个节点和174个连接），其中12个枢纽瓶颈节点具有两种药物氯喹和褪黑激素，与对应于6个上调和4个下调基因的10种蛋白质相关联。两种药物直接与枢纽瓶颈节点相互作用，即基质金属肽酶9（MMP 9），一种对应于其上调基因的宿主蛋白。MMP 9显示与中性粒细胞介导的免疫炎症相关的功能注释。此外，文献调查显示，SARS-CoV-2病毒的膜受体血管紧张素转换酶2可能与MMP 9具有功能协同性，并可能与两种药物发生相互作用。意义：本研究表明，在氯喹和褪黑素之间，褪黑素似乎是更有希望的抗MMP 9的再利用药物，以更好地改善COVID-19的免疫功能。
Aims: The molecular pathogenesis of COVID-19 is similar to other coronavirus (CoV) infections viz. severe acute respiratory syndrome (SARS) in human. Due to scarcity of the suitable treatment strategy, the present study was undertaken to explore host protein(s) targeted by potent repurposed drug(s) in COVID-19.Materials and methods: The differentially expressed genes (DEGs) were identified from microarray data repository of SARS-CoV patient blood. The repurposed drugs for COVID-19 were selected from available literature. Using DEGs and drugs, the protein-protein interaction (PPI) and chemo-protein interaction (CPI) networks were constructed and combined to develop an interactome model of PPI-CPI network. The top-ranked sub-network with its hub-bottleneck nodes were evaluated with their functional annotations.Key findings: A total of 120 DEGs and 65 drugs were identified. The PPI-CPI network (118 nodes and 293 edges) exhibited a top-ranked sub-network (35 nodes and 174 connectivities) with 12 hub-bottleneck nodes having two drugs chloroquine and melatonin in association with 10 proteins corresponding to six upregulated and four downregulated genes. Two drugs interacted directly with the hub-bottleneck node i.e. matrix metallopeptidase 9 (MMP9), a host protein corresponding to its upregulated gene. MMP9 showed functional annotations associated with neutrophil mediated immunoinflammation. Moreover, literature survey revealed that angiotensin converting enzyme 2, a membrane receptor of SARS-CoV-2 virus, might have functional cooperativity with MMP9 and a possible interaction with both drugs.Significance: The present study reveals that between chloroquine and melatonin, melatonin appears to be more promising repurposed drug against MMP9 for better immunocompromisation in COVID-19.