Chen Qishu, Zhou Qifan, Yang Sidi, Pan Fan, Tao Hongqi, Wen Yuanmei, Chao Yang, Xie Cailing, Ou Weixin, Guo Deyin, Li Yingjun, Zhang Xumu
Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, College of Science, Academy for Advanced Interdisciplinary Studies and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen, Guangdong 518000, China.
Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, College of Science, Academy for Advanced Interdisciplinary Studies and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen, Guangdong 518000, China.
Bioorg Chem. 2024 Dec;153:107894. doi: 10.1016/j.bioorg.2024.107894. Epub 2024 Oct 18.
Coronaviruses are RNA viruses that have coevolved with humans and animals over time, exhibiting high mutation rates and mortality rates upon epidemic outbreaks. The nonstructural protein (nsp14) is crucial for various coronaviruses processes, including genome replication, protein translation, virus particle assembly, and evasion of host immunity via RNA methylation modification. In this study, a series of adenosine analogs were designed, synthesized, and evaluated for their inhibitory activities. Among them, MTI013 exhibited the strongest nsp14 MTase inhibition and antiviral activity, with an IC of 10.33 μM in HCoV-229E-infected Huh7 cells, along with low cytotoxicity. When combined with the RdRp inhibitor ATV014, MTI013 showed a synergistic antiviral effect, indicating its potential both as a standalone therapy and in combination treatments. Furthermore, MTI013 displayed high selectivity against the SARS-CoV-2 nsp10-nsp16 complex and five human methyltransferases. These results offer valuable structural insights for future exploration of nsp14 as a drug target for SARS-CoV-2 and other coronaviruses.
冠状病毒是随着时间推移与人类和动物共同进化的RNA病毒，在疫情爆发时表现出高突变率和死亡率。非结构蛋白（nsp14）对各种冠状病毒过程至关重要，包括基因组复制、蛋白质翻译、病毒颗粒组装以及通过RNA甲基化修饰逃避宿主免疫。在本研究中，设计、合成并评估了一系列腺苷类似物的抑制活性。其中，MTI013表现出最强的nsp14甲基转移酶抑制作用和抗病毒活性，在感染HCoV - 229E的Huh7细胞中的IC50为10.33 μM，且细胞毒性较低。当与RdRp抑制剂ATV014联合使用时，MTI013显示出协同抗病毒作用，表明其作为单一疗法和联合治疗的潜力。此外，MTI013对SARS-CoV-2 nsp10 - nsp16复合物和五种人类甲基转移酶表现出高选择性。这些结果为未来将nsp14作为SARS-CoV-2和其他冠状病毒的药物靶点的探索提供了有价值的结构见解。
