Newly emerging or re-emerging viral infections continue to cause significant morbidity and mortality every year worldwide, resulting in serious effects on both health and the global economy. Despite significant drug discovery research against dengue viruses (DENVs) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), no fully effective and specific drugs directed against these viruses have been discovered. Here, we examined the anti-DENV activity of tubercidin derivatives from a compound library from Hokkaido University and demonstrated that 5-hydroxymethyltubercidin (HMTU, HUP1108) possessed both potent anti-flavivirus and anti-coronavirus activities at submicromolar levels without significant cytotoxicity. Furthermore, HMTU inhibited viral RNA replication and specifically inhibited replication at the late stages of the SARS-CoV-2 infection process. Finally, we demonstrated that HMTU 5′-triphosphate inhibited RNA extension catalyzed by the viral RNA-dependent RNA polymerase. Our findings suggest that HMTU has the potential of serving as a lead compound for the development of a broad spectrum of antiviral agents, including SARS-CoV-2.

全球每年新出现或重新出现的病毒感染继续造成显着的发病率和死亡率，对健康和全球经济造成严重影响。尽管针对登革热病毒 (DENV) 和严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 进行了重要的药物发现研究，但尚未发现针对这些病毒的完全有效和特异性的药物。在这里，我们检查了来自北海道大学化合物库的结核菌素衍生物的抗 DENV 活性，并证明 5-羟甲基结核菌素（HMTU，HUP1108）在亚微摩尔水平下具有有效的抗黄病毒和抗冠状病毒活性，而没有显着的细胞毒性。此外，HMTU 抑制病毒 RNA 复制，并在 SARS-CoV-2 感染过程的后期特别抑制复制。最后，我们证明 HMTU 5'-三磷酸抑制由病毒 RNA 依赖性 RNA 聚合酶催化的 RNA 延伸。我们的研究结果表明，HMTU 有潜力成为开发广谱抗病毒药物（包括 SARS-CoV-2）的先导化合物。