Discovery of a 2′-α-Fluoro-2′-β- C -(fluoromethyl) Purine Nucleotide Prodrug as a Potential Oral Anti-SARS-CoV-2 Agent

作者：Lan Liang, Yonggang Meng, Xiaoyu Chang, Ertong Li, Yucen Huang, Liming Yan, Zhiyong Lou, Youmei Peng, Bo Zhu, Wenquan Yu, Junbiao Chang · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.4c02769 · 被引用次数：10 · 研究领域：SARS-CoV-2 and COVID-19 Research、Virus-based gene therapy research、RNA Interference and Gene Delivery

A novel 2′-α-fluoro-2′-β- C -(fluoromethyl) purine nucleoside phosphoramidate prodrug 15 has been designed and synthesized to treat SARS-CoV-2 infection. The SARS-CoV-2 central replication transcription complex (C-RTC, nsp12-nsp7-nsp8 2 ) catalyzed in vitro RNA synthesis was effectively inhibited by the corresponding bioactive nucleoside triphosphate ( 13-TP ). The cryo-electron microscopy structure of the C-RTC: 13-TP complex was also determined. Compound 15 exhibited potent in vitro antiviral activity against the SARS-CoV-2 20SF107 strain (EC 50 = 0.56 ± 0.06 μM) and the Omicron BA.5 variant (EC 50 = 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 13-TP in the target organ lungs of rats with a long half-life. These findings support the further development of compound 15 as an orally available antiviral agent for the treatment of SARS-CoV-2 infection.