Nucleotide analogues as inhibitors of SARS-CoV Polymerase

Pharmacol Res Perspect. 2020 Dec;8(6):e00674. doi: 10.1002/prp2.674.


SARS-CoV-2, a member of the coronavirus family, has caused a global public health emergency. Based on our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously reasoned that the FDA-approved hepatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) should inhibit coronaviruses, including SARS-CoV-2. Here, using model polymerase extension experiments, we demonstrate that the active triphosphate form of Sofosbuvir is incorporated by low-fidelity polymerases and SARS-CoV RNA-dependent RNA polymerase (RdRp), and blocks further incorporation by these polymerases; the active triphosphate form of Sofosbuvir is not incorporated by a host-like high-fidelity DNA polymerase. Using the same molecular insight, we selected 3'-fluoro-3'-deoxythymidine triphosphate and 3'-azido-3'-deoxythymidine triphosphate, which are the active forms of two other anti-viral agents, Alovudine and AZT (an FDA-approved HIV/AIDS drug) for evaluation as inhibitors of SARS-CoV RdRp. We demonstrate the ability of two of these HIV reverse transcriptase inhibitors to be incorporated by SARS-CoV RdRp where they also terminate further polymerase extension. Given the 98% amino acid similarity of the SARS-CoV and SARS-CoV-2 RdRps, we expect these nucleotide analogues would also inhibit the SARS-CoV-2 polymerase. These results offer guidance to further modify these nucleotide analogues to generate more potent broad-spectrum anti-coronavirus agents.

Keywords: COVID-19; RNA-dependent RNA polymerase; SARS-CoV; SARS-CoV-2; nucleotide analogue.

MeSH terms

  • Antiviral Agents / pharmacology*
  • Betacoronavirus / drug effects*
  • Betacoronavirus / enzymology
  • COVID-19
  • Carbamates / pharmacology
  • Coronavirus Infections / drug therapy*
  • Coronavirus Infections / virology
  • Dideoxynucleotides / pharmacology
  • Drug Combinations
  • Heterocyclic Compounds, 4 or More Rings / pharmacology
  • Humans
  • Pandemics
  • Pneumonia, Viral / drug therapy*
  • Pneumonia, Viral / virology
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors*
  • SARS-CoV-2
  • Sofosbuvir / pharmacology
  • Thymine Nucleotides / pharmacology
  • Zidovudine / analogs & derivatives
  • Zidovudine / pharmacology


  • Antiviral Agents
  • Carbamates
  • Dideoxynucleotides
  • Drug Combinations
  • Heterocyclic Compounds, 4 or More Rings
  • Thymine Nucleotides
  • sofosbuvir-velpatasvir drug combination
  • 3'-fluorothymidine-5'-triphosphate
  • Zidovudine
  • zidovudine triphosphate
  • RNA-Dependent RNA Polymerase
  • Sofosbuvir