Publication date: Jan 13, 2025
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) 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 = 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 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.
| Concepts | Keywords |
|---|---|
| Antiviral | Agent |
| Bioactive | Antiviral |
| Fluoromethyl | Compound |
| Organ | Cov |
| Replication | Fluoro |
| Fluoromethyl | |
| Infection | |
| Nucleoside | |
| Oral | |
| Prodrug | |
| Purine | |
| Rtc | |
| Sars | |
| Tp |
Semantics
| Type | Source | Name |
|---|---|---|
| drug | DRUGBANK | Nebularine |
| disease | MESH | SARS-CoV-2 infection |
| pathway | REACTOME | SARS-CoV-2 Infection |
| disease | IDO | replication |