Shi Yu, Zhao Jianyuan, Li Min, Wei Liya, Shan Qi, Wang Minghua, Zhu Mei, Cen Shan, Zhang Guoning, Wang Juxian, Wang Yucheng
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China.
Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China.
Bioorg Med Chem. 2025 Jun 1;123:118153. doi: 10.1016/j.bmc.2025.118153. Epub 2025 Mar 7.
The COVID-19 pandemic has significantly strained global health infrastructures while profoundly affecting the socio-economic landscape. RNA-dependent RNA polymerase (RdRp) plays a pivotal role in the replication and transcription of RNA viruses, making it a critical target for antiviral drug development. In this work, we describe the discovery, rational optimization, and synthesis of a novel series of non-nucleoside SARS-CoV-2 RdRp inhibitors featuring a 2,2'-((1H-indole-2,3-diyl)bis (thio))diacetamide core. The inhibitory activity of these compounds was evaluated, with most demonstrating a higher inhibitory effect than Remdesivir. Notably, the most potent candidates suppressed RNA synthesis dose-dependently and exhibited greater resistance to nsp14/nsp10 exonuclease-mediated proofreading compared to Remdesivir. Furthermore, 10b6 and 10b12 showed 1.6- to 2-fold lower EC values against coronavirus HCoV-OC43 than Remdesivir, highlighting their potential for further development as broad-spectrum antiviral agents.
新冠疫情给全球卫生基础设施带来了巨大压力，同时对社会经济格局产生了深远影响。RNA依赖性RNA聚合酶（RdRp）在RNA病毒的复制和转录过程中起着关键作用，使其成为抗病毒药物研发的重要靶点。在这项工作中，我们描述了一系列以2,2'-((1H-吲哚-2,3-二基)双(硫代))二乙酰胺为核心的新型非核苷类SARS-CoV-2 RdRp抑制剂的发现、合理优化及合成。对这些化合物的抑制活性进行了评估，大多数化合物表现出比瑞德西韦更高的抑制效果。值得注意的是，最有效的候选化合物剂量依赖性地抑制RNA合成，并且与瑞德西韦相比，对nsp14/nsp10核酸外切酶介导的校对表现出更强的抗性。此外，10b6和10b12对冠状病毒HCoV-OC43的EC值比瑞德西韦低1.6至2倍，突出了它们作为广谱抗病毒药物进一步开发的潜力。
