Mechanism and spectrum of inhibition of viral polymerases by 2′-deoxy-2′-β-fluoro-4′-azidocytidine or azvudine

作者：Hery W. Lee, Egor P. Tchesnokov, Laura J. Stevens, Tia M. Hughes, Meghan V. Diefenbacher, Emma Woolner, Dana Kocíncová, D. Schultz, Sara Cherry, Timothy P. Sheahan, Mark R. Denison, Matthias Götte · 发表于：NAR Molecular Medicine · 年份：2025 · DOI：10.1093/narmme/ugaf029 · 被引用次数：7 · 研究领域：HIV/AIDS drug development and treatment、Biochemical and Molecular Research、HIV Research and Treatment

The therapeutic value of antiviral nucleoside analogs was highlighted during the coronavirus disease 2019 (COVID-19) pandemic, with remdesivir and molnupiravir repurposed for their broad-spectrum antiviral activity. The cytidine analog azvudine (FNC) has recently gained attention as a potential treatment for human immunodeficiency virus type 1 (HIV-1) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Considering the distinct substrate specificities of HIV-1 reverse transcriptase (RT) and SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), a unifying mechanism of inhibition remains elusive. Here, we assessed the inhibitory effects of FNC's active triphosphate form, FNC-TP, across several viral polymerases. The relative efficiency of FNC-TP incorporation followed the order: HIV-1 RT > hepatitis C virus (HCV) RdRp > respiratory syncytial virus (RSV) RdRp > dengue virus type 2 (DENV-2) RdRp ≫ SARS-CoV-2 RdRp. Its incorporation caused chain-termination in all polymerases tested. Antiviral activity against HIV-1 has previously been demonstrated and is here shown with DENV-2. Collectively, the data show that inhibition of viral polymerases by FNC-TP can translate to antiviral activity against both retroviruses and RNA viruses, but the link is not evident for SARS-CoV-2. FNC-TP is a poor substrate for SARS-CoV-2 RdRp, and FNC lacks significant antiviral activity against SARS-CoV-2 in cell culture.