A systems-level study reveals host-targeted repurposable drugs against SARS-CoV-2 infection.
A systems-level study reveals host-targeted repurposable drugs against SARS-CoV-2 infection.
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DOI：
10.15252/msb.202110239
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发表时间：
2021-08
影响因子：
9.9
通讯作者：
Bahar I
中科院分区：
文献类型：
--
作者：
Chen F;Shi Q;Pei F;Vogt A;Porritt RA;Garcia G Jr;Gomez AC;Cheng MH;Schurdak ME;Liu B;Chan SY;Arumugaswami V;Stern AM;Taylor DL;Arditi M;Bahar I
了解SARS - CoV - 2感染的机制并确定潜在的治疗方法是全球的当务之急。使用定量系统药理学方法，我们确定了一组可重复使用的研究药物作为抗COVID - 19的潜在治疗药物。这些结果是从SARS - CoV - 2感染的A549细胞的基因表达特征中推断出来的，这些细胞经过Connectivity Map筛选，并通过网络接近性分析对病毒-宿主相互作用组中的疾病模块进行了优先排序。我们还根据ACE2过表达A549细胞的转录组鉴定了旨在抑制严重COVID - 19患者高炎症反应的免疫调节化合物。用SARS‐CoV‐2感染的Vero‐E6细胞进行的实验，以及用HEK293T和Calu‐3细胞进行的探测ACE2/SARS‐CoV‐2刺突蛋白介导的细胞融合的独立合胞体形成实验表明，几种预测的化合物具有抑制活性。其中，沙美特罗、罗特列林和mTOR抑制剂在Vero‐E6细胞中表现出抗病毒活性；丙咪嗪、利西替尼、己基间二酚、依折麦比和溴苯那敏均可抑制病毒进入。这些新发现为扩大抗COVID - 19治疗药物的化合物库提供了新的途径。提出了一种系统药理学方法来鉴定靶向宿主细胞并具有抗SARS - CoV - 2作用的小分子和药物。通过实验验证入围候选药物。
Understanding the mechanism of SARS‐CoV‐2 infection and identifying potential therapeutics are global imperatives. Using a quantitative systems pharmacology approach, we identified a set of repurposable and investigational drugs as potential therapeutics against COVID‐19. These were deduced from the gene expression signature of SARS‐CoV‐2‐infected A549 cells screened against Connectivity Map and prioritized by network proximity analysis with respect to disease modules in the viral–host interactome. We also identified immuno‐modulating compounds aiming at suppressing hyperinflammatory responses in severe COVID‐19 patients, based on the transcriptome of ACE2‐overexpressing A549 cells. Experiments with Vero‐E6 cells infected by SARS‐CoV‐2, as well as independent syncytia formation assays for probing ACE2/SARS‐CoV‐2 spike protein‐mediated cell fusion using HEK293T and Calu‐3 cells, showed that several predicted compounds had inhibitory activities. Among them, salmeterol, rottlerin, and mTOR inhibitors exhibited antiviral activities in Vero‐E6 cells; imipramine, linsitinib, hexylresorcinol, ezetimibe, and brompheniramine impaired viral entry. These novel findings provide new paths for broadening the repertoire of compounds pursued as therapeutics against COVID‐19. A systems pharmacology approach is proposed to identify small molecules and drugs that target host cells and have anti‐SARS‐CoV‐2 effects. Shortlisted drug candidates are experimentally validated.