The global efforts in the past few months have led to the discovery of around 200 drug repurposing candidates for COVID-19. Although most of them only exhibited moderate anti-SARS-CoV-2 activity, gaining more insights into their mechanisms of action could facilitate a better understanding of infection and the development of therapeutics. Leveraging large-scale drug-induced gene expression profiles, we found 36% of the active compounds regulate genes related to cholesterol homeostasis and microtubule cytoskeleton organization. The expression change upon drug treatment was further experimentally confirmed in human lung primary small airway. Following bioinformatics analysis on COVID-19 patient data revealed that these genes are associated with COVID-19 patient severity. The expression level of these genes also has predicted power on anti-SARS-CoV-2 efficacy in vitro, which led to the discovery of monensin as an inhibitor of SARS-CoV-2 replication in Vero-E6 cells. The final survey of recent drug-combination data indicated that drugs co-targeting cholesterol homeostasis and microtubule cytoskeleton organization processes more likely present a synergistic effect with antivirals. Therefore, potential therapeutics should be centered around combinations of targeting these processes and viral proteins.

中文翻译：

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已发表的抗 SARS-CoV-2 体外打击具有与抗病毒药物协同作用的共同作用机制

过去几个月的全球努力导致发现了大约 200 种 COVID-19 药物再利用候选药物。尽管它们中的大多数仅表现出适度的抗 SARS-CoV-2 活性，但对其作用机制的深入了解有助于更好地了解感染和治疗方法的开发。利用大规模药物诱导的基因表达谱，我们发现 36% 的活性化合物调节与胆固醇稳态和微管细胞骨架组织相关的基因。药物治疗后的表达变化在人肺初级小气道中得到了进一步的实验证实。对 COVID-19 患者数据进行生物信息学分析后发现，这些基因与 COVID-19 患者的严重程度相关。这些基因的表达水平也预测了体外抗 SARS-CoV-2 效力的能力，从而导致发现莫能菌素作为 Vero-E6 细胞中 SARS-CoV-2 复制的抑制剂。最近的药物组合数据的最终调查表明，共同靶向胆固醇稳态和微管细胞骨架组织过程的药物更有可能与抗病毒药物产生协同作用。因此，潜在的治疗方法应该集中在靶向这些过程和病毒蛋白的组合上。最近的药物组合数据的最终调查表明，共同靶向胆固醇稳态和微管细胞骨架组织过程的药物更有可能与抗病毒药物产生协同作用。因此，潜在的治疗方法应该集中在靶向这些过程和病毒蛋白的组合上。最近的药物组合数据的最终调查表明，共同靶向胆固醇稳态和微管细胞骨架组织过程的药物更有可能与抗病毒药物产生协同作用。因此，潜在的治疗方法应该集中在靶向这些过程和病毒蛋白的组合上。