Laboratory of Biomolecular Science, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Drug Discovery and Disease Research Laboratory, Shionogi & Co. Ltd., Osaka 561-0825, Japan.
Proc Natl Acad Sci U S A. 2023 Oct 17;120(42):e2304139120. doi: 10.1073/pnas.2304139120. Epub 2023 Oct 13.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are causing significant morbidity and mortality worldwide. Furthermore, over 1 million cases of newly emerging or re-emerging viral infections, specifically dengue virus (DENV), are known to occur annually. Because no virus-specific and fully effective treatments against these or many other viruses have been approved, there is an urgent need for novel, effective therapeutic agents. Here, we identified 2-thiouridine (s2U) as a broad-spectrum antiviral ribonucleoside analogue that exhibited antiviral activity against several positive-sense single-stranded RNA (ssRNA+) viruses, such as DENV, SARS-CoV-2, and its variants of concern, including the currently circulating Omicron subvariants. s2U inhibits RNA synthesis catalyzed by viral RNA-dependent RNA polymerase, thereby reducing viral RNA replication, which improved the survival rate of mice infected with DENV2 or SARS-CoV-2 in our animal models. Our findings demonstrate that s2U is a potential broad-spectrum antiviral agent not only against DENV and SARS-CoV-2 but other ssRNA+ viruses.
严重急性呼吸系统综合症冠状病毒 2（SARS-CoV-2）的感染正在全球范围内造成重大的发病率和死亡率。此外，每年已知有超过 100 万例新出现或再现的病毒感染，特别是登革热病毒（DENV）。由于没有针对这些或许多其他病毒的特定的、完全有效的治疗方法已经被批准，因此迫切需要新型有效的治疗药物。在这里，我们鉴定出 2-硫尿嘧啶（s2U）作为一种广谱抗病毒核苷类似物，对几种正链单链 RNA（ssRNA+）病毒具有抗病毒活性，例如 DENV、SARS-CoV-2 及其关注的变体，包括目前流行的奥密克戎亚变体。s2U 抑制由病毒 RNA 依赖性 RNA 聚合酶催化的 RNA 合成，从而减少病毒 RNA 的复制，这提高了我们动物模型中感染 DENV2 或 SARS-CoV-2 的小鼠的存活率。我们的研究结果表明，s2U 不仅是一种针对 DENV 和 SARS-CoV-2 的潜在广谱抗病毒药物，也是针对其他 ssRNA+病毒的潜在广谱抗病毒药物。
