论文标题
人类细胞中冠状病毒靶标的基因组指导的分子图：现有药物的重新利用的路径减轻大流行
Genomics-guided molecular maps of coronavirus targets in human cells: a path toward the repurposing of existing drugs to mitigate the pandemic
论文作者
论文摘要
SARS-COV-2进入人类细胞所需的人类基因ACE2和FURIN被用作诱饵来构建上游调节元件的基因组引导图，它们在人体中的表达和功能，包括病理生理学的细胞类型。基于基因沉默和过表达实验的分析以及相关的转基因小鼠模型，鉴定出充当ACE2和FURIN基因的阻遏物和激活因子的基因。然后使用阻遏物（VDR； GATA5； SFTPC； HIF1A）和激活剂（HMGA2； INGIG1）的面板来鉴定可重新使用以减轻冠状病毒感染的现有药物。目前的分析将维生素D和槲皮素鉴定为有前途的大流行缓解剂。维生素D和槲皮素活性的基因表达谱及其既定的安全记录作为非处方药物，表明它们可能代表可行的候选者，以进一步评估和考虑其作为冠状病毒大流行缓解剂的潜力。值得注意的是，基因集富集分析和表达分析实验鉴定了多种药物，最著名的是睾丸激素，地塞米松和阿霉素，吸烟以及许多似乎充当推定冠状病毒感染剂的疾病。睾丸激素与雌二醇对Scars-Cov-2靶标的影响不一致的模式表明，在冠状病毒大流行期间，男性死亡率显然更高的分子解释。
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.
