Saito-Tarashima Noriko, Koma Takaaki, Hinotani Naoto, Yoshida Keigo, Ogasa Moka, Murai Akiho, Inoue Syuya, Kondo Tomoyuki, Doi Naoya, Tsuneyama Koichi, Nomaguchi Masako, Minakawa Noriaki
Graduate School of Pharmaceutical Science, Tokushima University, 1-78-1 Shomachi, Tokushima, Tokushima 770-8505, Japan.
Department of Microbiology, Graduate School of Medicine, Tokushima University, 3-18-15 Kuramoto, Tokushima, Tokushima 770-8503, Japan.
iScience. 2025 Mar 1;28(4):112140. doi: 10.1016/j.isci.2025.112140. eCollection 2025 Apr 18.
The COVID-19 pandemic highlighted the serious threat that coronaviruses have on public health. Because coronavirus continuously undergoes cross-species transmission, additional therapeutic agents and targets are urgently needed. Here, we show that a 3-deazapurine ribonucleoside, 3-Deazaguanosine (CGuo, ), has potent antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Unexpectedly, CGuo () does not act as an inhibitor of RNA-dependent RNA polymerase (RdRp), which is the therapeutic target of two key nucleoside/nucleotide inhibitors approved for the treatment of COVID-19 (Remdesivir and Molnupiravir); instead, it seems to function by targeting the capping machinery of viral RNA. In hamsters infected with SARS-CoV-2, administration of markedly reduced infectious viral titers, and prevented the development of COVID-19 pneumonia better than Molnupiravir. The potency of against SARS-CoV-2 underscores its potential as an effective therapeutic agent for COVID-19 and future zoonotic coronavirus infections and raises the possibility of antiviral nucleoside analogs with alternative therapeutic targets to RdRp.
新冠疫情凸显了冠状病毒对公共卫生构成的严重威胁。由于冠状病毒不断发生跨物种传播，迫切需要更多的治疗药物和靶点。在此，我们表明一种3-脱氮嘌呤核糖核苷，3-脱氮鸟苷（CGuo），对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）具有强大的抗病毒活性。出乎意料的是，CGuo并不作为RNA依赖性RNA聚合酶（RdRp）的抑制剂发挥作用，而RdRp是两种被批准用于治疗新冠的关键核苷/核苷酸抑制剂（瑞德西韦和莫努匹韦）的治疗靶点；相反，它似乎是通过靶向病毒RNA的加帽机制发挥作用。在感染SARS-CoV-2的仓鼠中，给予CGuo显著降低了感染性病毒滴度，并且比莫努匹韦更有效地预防了新冠肺炎的发展。CGuo对SARS-CoV-2的效力凸显了其作为新冠及未来人畜共患冠状病毒感染的有效治疗药物的潜力，并增加了具有RdRp替代治疗靶点的抗病毒核苷类似物的可能性。
