[论文解读] Genomics-guided molecular maps of coronavirus targets in human cells: a path toward the repurposing of existing drugs to mitigate the pandemic

Gennadi V. Glinsky|arXiv (Cornell University)|Mar 30, 2020

SARS-CoV-2 and COVID-19 Research参考文献 18被引用 13

一句话总结

本研究通过基因组引导的宿主因子调控SARS-CoV-2进入相关基因ACE2和FURIN的图谱分析，识别出可能减轻感染的现有药物。通过分析基因调控因子和药物效应，确定了维生素D和槲皮素为有前景的候选药物，同时提示睾酮和地塞米松可能为感染促进因素，为疫情防控提供了药物重定位策略。

ABSTRACT

Human genes required for SARS-CoV-2 entry into human cells, ACE2 and FURIN, were employed as baits to build genomics-guided maps of up-stream regulatory elements, their expression and functions in human body, including pathophysiologically-relevant cell types. Genes acting as repressors and activators of the ACE2 and FURIN genes were identified based on the analyses of gene silencing and overexpression experiments as well as relevant transgenic mouse models. Panels of repressors (VDR; GATA5; SFTPC; HIF1a) and activators (HMGA2; INSIG1) were then employed to identify existing drugs that could be repurposed to mitigate the coronavirus infection. Present analyses identify Vitamin D and Quercetin as promising pandemic mitigation agents. Gene expression profiles of Vitamin D and Quercetin activities and their established safety records as over-the-counter medicinal substances suggest that they may represent viable candidates for further assessment and considerations of their potential as coronavirus pandemic mitigation agents. Notably, gene set enrichment analyses and expression profiling experiments identify multiple drugs, most notably testosterone, dexamethasone, and doxorubicin, smoking, and many disease conditions that appear to act as putative coronavirus infection-promoting agents. Discordant patterns of Testosterone versus Estradiol impacts on SCARS-CoV-2 targets suggest a plausible molecular explanation of the apparently higher male mortality during coronavirus pandemic.

研究动机与目标

• 识别调控ACE2和FURIN（SARS-CoV-2进入关键基因）的宿主细胞因子。
• 绘制人类组织中ACE2和FURIN的上游调控元件及功能网络图谱。
• 识别可通过其调控网络调节ACE2和FURIN表达的现有药物。
• 基于基因组和表达数据，评估重定位药物减轻冠状病毒感染的潜力。
• 通过病毒靶点的激素调控，探讨感染易感性的性别差异。

提出的方法

• 以ACE2和FURIN为探针，构建基因组引导的调控元件和基因网络分子图谱。
• 分析基因沉默和过表达数据，以及转基因小鼠模型，识别ACE2和FURIN的抑制因子和激活因子。
• 整合基因集富集分析和表达谱分析，将药物活性与病毒进入基因的调控网络关联。
• 基于已知药物对鉴定出的调控因子的影响评估现有药物，重点关注安全性和药物重定位潜力。
• 评估激素影响（睾酮、雌二醇）对病毒靶点表达的作用，以解释感染结局的性别差异。

实验结果

研究问题

• RQ1 哪些宿主基因调控人细胞中ACE2和FURIN的表达，其如何影响SARS-CoV-2的进入？
• RQ2 哪些现有药物可通过其调控网络调节ACE2和FURIN的表达？
• RQ3 已知安全的药物如维生素D和槲皮素是否可被重定位以降低SARS-CoV-2感染风险？
• RQ4 睾酮和雌二醇等性激素在调控病毒进入因子中起何种作用？
• RQ5 哪些药物或条件可能通过上调ACE2或FURIN而意外促进SARS-CoV-2感染？

主要发现

• 维生素D和槲皮素因其对ACE2和FURIN的调控作用及已确立的安全性，被确定为减轻SARS-CoV-2感染的有前景候选药物。
• 抑制因子组包括VDR、GATA5、SFTPC和HIF1a，而HMGA2和INSIG1被鉴定为ACE2和FURIN表达的激活因子。
• 睾酮可能通过上调病毒进入因子促进感染，为男性死亡率更高的现象提供了分子解释。
• 地塞米松和多柔比星基于其对调控网络的影响，被识别为潜在的感染促进剂。
• 吸烟也被认为可能通过与病毒进入基因共享的调控通路而促进感染。
• 睾酮与雌二醇对SCARS-CoV-2靶点的相反作用提示了疾病严重程度性别差异的合理生物学基础。