Liang Lan, Meng Yonggang, Chang Xiaoyu, Li Ertong, Huang Yucen, Yan Liming, Lou Zhiyong, Peng Youmei, Zhu Bo, Yu Wenquan, Chang Junbiao
State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, NMPA Key Laboratory for Research and Evaluation of Innovative Drug, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, China.
State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, College of Chemistry, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
J Med Chem. 2025 Jan 23;68(2):1994-2007. doi: 10.1021/acs.jmedchem.4c02769. Epub 2025 Jan 13.
A novel 2'-α-fluoro-2'-β--(fluoromethyl) purine nucleoside phosphoramidate prodrug has been designed and synthesized to treat SARS-CoV-2 infection. The SARS-CoV-2 central replication transcription complex (C-RTC, nsp12-nsp7-nsp8) catalyzed in vitro RNA synthesis was effectively inhibited by the corresponding bioactive nucleoside triphosphate (). The cryo-electron microscopy structure of the C-RTC: complex was also determined. Compound exhibited potent in vitro antiviral activity against the SARS-CoV-2 20SF107 strain (EC = 0.56 ± 0.06 μM) and the Omicron BA.5 variant (EC = 0.96 ± 0.23 μM) with low cytotoxicity. Furthermore, it was well tolerated in rats at doses of up to 2000 mg/kg, and a single oral dose of this prodrug at 40 mg/kg led to high levels of in the target organ lungs of rats with a long half-life. These findings support the further development of compound as an orally available antiviral agent for the treatment of SARS-CoV-2 infection.
一种新型的2'-α-氟-2'-β-(氟甲基)嘌呤核苷亚磷酰胺前药已被设计并合成用于治疗SARS-CoV-2感染。相应的生物活性核苷三磷酸有效抑制了SARS-CoV-2中央复制转录复合体（C-RTC，nsp12-nsp7-nsp8）催化的体外RNA合成。还确定了C-RTC:复合体的冷冻电子显微镜结构。化合物对SARS-CoV-2 20SF107毒株（EC = 0.56 ± 0.06 μM）和奥密克戎BA.5变体（EC = 0.96 ± 0.23 μM）表现出强大的体外抗病毒活性，且细胞毒性低。此外，在大鼠中，高达2000 mg/kg的剂量下耐受性良好，该前药40 mg/kg的单次口服剂量导致大鼠靶器官肺中的 水平较高，半衰期较长。这些发现支持将化合物 进一步开发为用于治疗SARS-CoV-2感染的口服抗病毒药物。
