COVID-19 is a highly contagious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The case-fatality rate is significantly higher in older patients and those with diabetes, cancer or cardiovascular disorders. The human proteins, angiotensin-converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2) and basigin (BSG), are involved in high-confidence host-pathogen interactions with SARS-CoV-2 proteins. We considered these three proteins as seed nodes and applied the random walk with restart method on the human interactome to construct a protein-protein interaction sub-network, which captures the effects of viral invasion. We found that ‘Insulin resistance’, ‘AGE-RAGE signaling in diabetic complications’ and ‘adipocytokine signaling’ were the common pathways associated with diabetes, cancer and cardiovascular disorders. The association of these critical pathways with aging and its related diseases explains the molecular basis of COVID-19 fatality. We further identified drugs that have effects on these proteins/pathways based on gene expression studies. We particularly focused on drugs that significantly downregulate ACE2 along with other critical proteins identified by the network-based approach. Among them, COL-3 had earlier shown activity against acute lung injury and acute respiratory distress, while entinostat and mocetinostat have been investigated for non-small-cell lung cancer. We propose that these drugs can be repurposed for COVID-19.

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基于网络的 COVID-19 致命合并症和潜在治疗方法分析

COVID-19 是一种由严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 引起的高度传染性疾病。老年患者和糖尿病、癌症或心血管疾病患者的病死率明显更高。人类蛋白质、血管紧张素转换酶 2 (ACE2)、跨膜蛋白酶丝氨酸 2 (TMPRSS2) 和 basigin (BSG) 参与了与 SARS-CoV-2 蛋白质的高度可信的宿主-病原体相互作用。我们将这三种蛋白质视为种子节点，并在人类相互作用组上应用带有重启的随机游走方法来构建蛋白质-蛋白质相互作用子网络，该子网络捕获病毒入侵的影响。我们发现“胰岛素抵抗”、“糖尿病并发症中的 AGE-RAGE 信号传导”和“脂肪细胞因子信号传导”是与糖尿病相关的常见途径，癌症和心血管疾病。这些关键途径与衰老及其相关疾病的关联解释了 COVID-19 致死的分子基础。我们根据基因表达研究进一步确定了对这些蛋白质/途径有影响的药物。我们特别关注显着下调 ACE2 以及通过基于网络的方法确定的其他关键蛋白质的药物。其中，COL-3 较早表现出对急性肺损伤和急性呼吸窘迫的活性，而恩替司他和莫西替他已被研究用于治疗非小细胞肺癌。我们建议这些药物可以重新用于 COVID-19。我们根据基因表达研究进一步确定了对这些蛋白质/途径有影响的药物。我们特别关注显着下调 ACE2 以及通过基于网络的方法确定的其他关键蛋白质的药物。其中，COL-3 较早表现出对急性肺损伤和急性呼吸窘迫的活性，而恩替司他和莫西替他已被研究用于治疗非小细胞肺癌。我们建议这些药物可以重新用于 COVID-19。我们根据基因表达研究进一步确定了对这些蛋白质/途径有影响的药物。我们特别关注显着下调 ACE2 以及通过基于网络的方法确定的其他关键蛋白质的药物。其中，COL-3 较早表现出对急性肺损伤和急性呼吸窘迫的活性，而恩替司他和莫西替他已被研究用于治疗非小细胞肺癌。我们建议这些药物可以重新用于 COVID-19。而恩替司他和莫西司他已被研究用于治疗非小细胞肺癌。我们建议这些药物可以重新用于 COVID-19。而恩替司他和莫西司他已被研究用于治疗非小细胞肺癌。我们建议这些药物可以重新用于 COVID-19。