Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Shenyang, China.
Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, China.
Drug Dev Res. 2024 Aug;85(5):e22237. doi: 10.1002/ddr.22237.
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) value of 9.95 μM, which was superior to that of ribavirin (the positive control, IC = 11.43 μM). Moreover, 38a also has inhibitory activity against coronavirus 229E with an IC 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.
近年来，RNA 病毒感染的全球流行对公共卫生提出了重大挑战，这就需要扩大其替代治疗药物库。由于其进化保守性，RNA 依赖性 RNA 聚合酶（RdRp）已成为广谱抗病毒核苷类似物的潜在靶标。然而，经过半个多世纪的结构修饰，使用常用的结构取代方法探索未被开发的化学空间来设计新的核苷类似物具有挑战性。在这项研究中，我们探索了使用“开环”策略来设计新的碱基类似物，从而使用这些碱基类似物设计具有广谱抗病毒活性的新核苷类似物。共合成了 29 种化合物。最初使用甲型流感病毒 RdRp 高通量筛选模型筛选它们对病毒 RdRp 的活性。然后，验证了 38a 对流感病毒 A/PR/8/34（H1N1）株的抗病毒活性，其 50%抑制浓度（IC）值为 9.95μM，优于利巴韦林（阳性对照，IC=11.43μM）。此外，38a 对冠状病毒 229E 也具有抑制活性，IC 为 30.82μM。此外，化合物 42 和 46f 在 20μM 浓度下对水疱性口炎病毒的抑制率达到 82%，并且在宿主细胞中几乎没有诱导细胞毒性。这项工作证明了用“开环”碱基设计核苷类似物的可行性，并表明“开环”核苷可能具有更大的极性，设计前药是优化其抗病毒活性的一个重要方面。未来的研究应集中于增强开环碱基的构象限制，以更好地模拟沃森-克里克碱基配对，并提高抗病毒活性。
