School of Physics and Physical Engineering, Qufu Normal University, Qufu, 273165, PR China; Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China.
Key Laboratory of Green Natural Products and Pharmaceutical Intermediates in Colleges and Universities of Shandong Province, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu, 273165, PR China; School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus, Chemistry & Chemical Biology (Ministry of Education), Tsinghua University, Beijing, 100084, PR China.
Eur J Med Chem. 2023 Sep 5;257:115503. doi: 10.1016/j.ejmech.2023.115503. Epub 2023 May 18.
The ongoing COVID-19 pandemic has resulted in millions of deaths globally, highlighting the need to develop potent prophylactic and therapeutic strategies against SARS-CoV-2. Small molecule inhibitors (remdesivir, Paxlovid, and molnupiravir) are essential complements to vaccines and play important roles in clinical treatment of SARS-CoV-2. Many advances have been made in development of anti-SARS-CoV-2 inhibitors in China, but progress in discovery and characterization of pharmacological activity, antiviral mechanisms, and clinical efficacy are limited. We review development of small molecule anti-SARS-CoV-2 drugs (azvudine [approved by the NMPA of China on July 25, 2022], VV116 [approved by the NMPA of China on January 29, 2023], FB2001, WPV01, pentarlandir, and cepharanthine) in China and summarize their pharmacological activity, potential mechanisms of action, clinical trials and use, and important milestones in their discovery. The role of structural biology in drug development is also reviewed. Future studies should focus on development of diverse second-generation inhibitors with excellent oral bioavailability, superior plasma half-life, increased antiviral activity against SARS-CoV-2 and its variants, high target specificity, minimal side effects, reduced drug-drug interactions, and improved lung histopathology.
持续的 COVID-19 大流行已在全球范围内导致数百万人死亡，这凸显了开发针对 SARS-CoV-2 的有效预防和治疗策略的必要性。小分子抑制剂（瑞德西韦、Paxlovid 和莫努匹韦）是疫苗的重要补充，在 SARS-CoV-2 的临床治疗中发挥着重要作用。中国在开发抗 SARS-CoV-2 抑制剂方面取得了许多进展，但在发现和表征药理活性、抗病毒机制和临床疗效方面的进展有限。我们综述了中国开发的小分子抗 SARS-CoV-2 药物（阿兹夫定[于 2022 年 7 月 25 日获国家药品监督管理局批准]、VV116[于 2023 年 1 月 29 日获国家药品监督管理局批准]、FB2001、WPV01、戊烷脒和长春西汀）的进展，总结了它们的药理活性、潜在作用机制、临床试验和应用，以及在发现过程中的重要里程碑。还回顾了结构生物学在药物开发中的作用。未来的研究应集中开发具有良好口服生物利用度、更长血浆半衰期、对 SARS-CoV-2 及其变体更高的抗病毒活性、高靶标特异性、最小副作用、减少药物相互作用和改善肺部组织病理学的多样化第二代抑制剂。
