Gao Minli, Zhang Zhaoyong, Yao Guoqiang, Zhang Lu, Duan Anna, Zhang Yuanyuan, Wang Yanqun, Zhao Jincun, Zhang Jiancun
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, Guangzhou, 510530, China; University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing, 100049, China.
State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
Antiviral Res. 2025 Feb;234:106060. doi: 10.1016/j.antiviral.2024.106060. Epub 2024 Dec 30.
The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused an unprecedented global public health crisis and continues to pose grave threats to human health. The efficacy of current vaccines and therapeutics is likely limited for future emerging strains due to the highly mutative nature of the virus, underscoring an urgent need for the development of new, potent antiviral agents. In this study, we report the design and synthesis of a series of novel 2'-deoxy-2'-spirooxetane-7-deazapurine nucleoside analogs as potential inhibitors of SARS-CoV-2 replication. Some of these compounds demonstrate potent antiviral activity, offering a potential new weapon for therapeutic intervention against the ever-evolving SARS-CoV-2 virus. Among the tested compounds, nucleoside analog 11q exhibited the most potent antiviral activity against SARS-CoV-2 in Vero E6 cells, with IC values of 0.14 μM for the wild-type strain and 0.36 μM for the BA.5 strain. Notably, compound 11q exhibits up to nine times greater inhibitory activity against wild-type SARS-CoV-2 compared to Remdesivir and also possesses a superior selectivity index. These findings suggest that compound 11q is a highly promising lead candidate for future drug development aimed at combating SARS-CoV-2.
由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引起的新冠疫情，已造成一场前所未有的全球公共卫生危机，并继续对人类健康构成严重威胁。由于该病毒具有高度的变异性，当前疫苗和治疗方法对未来出现的毒株的效力可能有限，这凸显了开发新型高效抗病毒药物的迫切需求。在本研究中，我们报告了一系列新型2'-脱氧-2'-螺氧杂环丁烷-7-脱氮嘌呤核苷类似物的设计与合成，它们是潜在的SARS-CoV-2复制抑制剂。其中一些化合物表现出强大的抗病毒活性，为针对不断演变的SARS-CoV-2病毒的治疗干预提供了一种潜在的新武器。在测试的化合物中，核苷类似物11q在Vero E6细胞中对SARS-CoV-2表现出最强大的抗病毒活性，对野生型毒株的IC值为0.14 μM，对BA.5毒株的IC值为0.36 μM。值得注意的是，与瑞德西韦相比，化合物11q对野生型SARS-CoV-2的抑制活性高出多达九倍，并且还具有更高的选择性指数。这些发现表明，化合物11q是未来对抗SARS-CoV-2药物开发的极具潜力的先导候选物。
