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

  • NAR Mol Med. 2025 Aug 11;2(3):ugaf029. doi: 10.1093/narmme/ugaf029.
Hery W Lee  1 ,  Egor P Tchesnokov  1 ,  Laura J Stevens  2 ,  Tia M Hughes  2 ,  Meghan V Diefenbacher  3 ,  Emma Woolner  1 ,  Dana Kocincova  1 ,  David C Schultz  4 ,  Sara Cherry  4  5 ,  Timothy P Sheahan  3 ,  Mark R Denison  2  6  7 ,  Matthias Götte  1
Affiliations
  • 1. Department of Medical Microbiology & Immunology, University of Alberta, Edmonton, AB T6G 2E1, Canada.
  • 2. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
  • 3. Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States.
  • 4. Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, United States.
  • 5. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States.
  • 6. Vanderbilt Institute for Infection, Immunology, and Inflammation, Nashville, TN 37232, United States.
  • 7. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
PMID: 40900943 DOI: 10.1093/narmme/ugaf029
Abstract

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.

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