核苷
法维皮拉维
核苷类似物
病毒
前药
水泡性口炎病毒
合理设计
立体化学
甲型流感病毒
结构-活动关系
生物
RNA聚合酶
化学
病毒学
核糖核酸
生物化学
基因
体外
医学
传染病(医学专业)
2019年冠状病毒病(COVID-19)
遗传学
疾病
病理
作者
Xingyi Du,Xingxing Yang,Jian‐Yuan Zhao,Shouxin Zhang,Jiahui Yu,Ling Ma,Weina Zhang,Shan Cen,Xuhong Ren,Xinhua He
摘要
Abstract The global prevalence of RNA virus infections has presented significant challenges to public health in recent years, necessitating the expansion of its alternative therapeutic library. Due to its evolutional conservation, RNA‐dependent RNA polymerase (RdRp) has emerged as a potential target for broad‐spectrum antiviral nucleoside analogues. However, after over half a century of structural modification, exploring unclaimed chemical space using frequently‐used structural substitution methods to design new nucleoside analogues is challenging. In this study, we explore the use of the “ring‐opening” strategy to design new base mimics, thereby using these base mimics to design new nucleoside analogues with broad‐spectrum antiviral activities. A total of 29 compounds were synthesized. Their activity against viral RdRp was initially screened using an influenza A virus RdRp high‐throughput screening model. Then, the antiviral activity of 38a was verified against influenza virus strain A/PR/8/34 (H1N1), demonstrating a 50% inhibitory concentration (IC 50 ) value of 9.95 μM, which was superior to that of ribavirin (the positive control, IC 50 = 11.43 μM). Moreover, 38a also has inhibitory activity against coronavirus 229E with an IC 50 of 30.82 μM. In addition, compounds 42 and 46f exhibit an 82% inhibition rate against vesicular stomatitis virus at a concentration of 20 μM and hardly induce cytotoxicity in host cells. This work demonstrates the feasibility of designing nucleoside analogues with “ring‐opening” bases and suggests the “ring‐opening” nucleosides may have greater polarity, and designing prodrugs is an important aspect of optimizing their antiviral activity. Future research should focus on enhancing the conformational restriction of open‐loop bases to mimic Watson‐Crick base pairing better and improve antiviral activity.
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