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

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.