Coronavirus disease 2019 (COVID-19) is a newly emerged infectious disease caused by a novel coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The rapid global emergence of SARS-CoV-2 highlights the importance and urgency for potential drugs to control the pandemic. The functional importance of RNA-dependent RNA polymerase (RdRp) in the viral life cycle, combined with structural conservation and absence of closely related homologs in humans, makes it an attractive target for designing antiviral drugs. Nucleos(t)ide analogs (NAs) are still the most promising broad-spectrum class of viral RdRp inhibitors. In this study, using our previously developed cell-based SARS-CoV-2 RdRp report system, we screened 134 compounds in the Selleckchemicals NAs library. Four candidate compounds, Fludarabine Phosphate, Fludarabine, 6-Thio-20-Deoxyguanosine (6-Thio-dG), and 5-Iodotubercidin, exhibit remarkable potency in inhibiting SARS-CoV-2 RdRp. Among these four compounds, 5-Iodotubercidin exhibited the strongest inhibition upon SARS-CoV-2 RdRp, and was resistant to viral exoribonuclease activity, thus presenting the best antiviral activity against coronavirus from a different genus. Further study showed that the RdRp inhibitory activity of 5-Iodotubercidin is closely related to its capacity to inhibit adenosine kinase (ADK).

冠状病毒病 2019（COVID-19）是由新型冠状病毒严重急性呼吸系统综合症冠状病毒 2（SARS-CoV-2）引起的新发传染病。SARS-CoV-2 在全球的迅速出现凸显了寻找潜在药物控制大流行的重要性和紧迫性。依赖于 RNA 的 RNA 聚合酶 (RdRp) 在病毒生命周期中的功能重要性，加上结构保守和在人类中缺乏密切相关的同系物，使其成为设计抗病毒药物的有吸引力的目标。核苷（酸）类似物 (NA) 仍然是最有前途的广谱病毒 RdRp 抑制剂。在这项研究中，我们使用我们之前开发的基于细胞的 SARS-CoV-2 RdRp 报告系统，筛选了 Selleckchemicals NAs 库中的 134 种化合物。四种候选化合物，Fludarabine Phosphate, Fludarabine, 6-Thio-20-Deoxyguanosine (6-Thio-dG) 和 5-Iodotubercidin 在抑制 SARS-CoV-2 RdRp 方面表现出显着的效力。在这四种化合物中，5-Iodotubercidin 对 SARS-CoV-2 RdRp 的抑制作用最强，并且对病毒外核糖核酸酶活性具有抗性，因此对不同属的冠状病毒表现出最好的抗病毒活性。进一步研究表明，5-Iodotubercidin 的 RdRp 抑制活性与其抑制腺苷激酶 (ADK) 的能力密切相关。