The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus

J Biol Chem. 2020 Apr 10;295(15):4773-4779. doi: 10.1074/jbc.AC120.013056. Epub 2020 Feb 24.


Antiviral drugs for managing infections with human coronaviruses are not yet approved, posing a serious challenge to current global efforts aimed at containing the outbreak of severe acute respiratory syndrome-coronavirus 2 (CoV-2). Remdesivir (RDV) is an investigational compound with a broad spectrum of antiviral activities against RNA viruses, including severe acute respiratory syndrome-CoV and Middle East respiratory syndrome (MERS-CoV). RDV is a nucleotide analog inhibitor of RNA-dependent RNA polymerases (RdRps). Here, we co-expressed the MERS-CoV nonstructural proteins nsp5, nsp7, nsp8, and nsp12 (RdRp) in insect cells as a part a polyprotein to study the mechanism of inhibition of MERS-CoV RdRp by RDV. We initially demonstrated that nsp8 and nsp12 form an active complex. The triphosphate form of the inhibitor (RDV-TP) competes with its natural counterpart ATP. Of note, the selectivity value for RDV-TP obtained here with a steady-state approach suggests that it is more efficiently incorporated than ATP and two other nucleotide analogs. Once incorporated at position i, the inhibitor caused RNA synthesis arrest at position i + 3. Hence, the likely mechanism of action is delayed RNA chain termination. The additional three nucleotides may protect the inhibitor from excision by the viral 3'-5' exonuclease activity. Together, these results help to explain the high potency of RDV against RNA viruses in cell-based assays.

Keywords: Ebola virus (EBOV); Middle East respiratory syndrome coronavirus (MERS–CoV); RNA chain termination; RNA-dependent RNA polymerase (RdRp); SARS–CoV-2; antiviral drug; coronavirus; drug development; enzyme inhibitor; nucleoside/nucleotide analog; plus-stranded RNA virus; positive-sense RNA virus; remdesivir; viral polymerase; viral replicase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Monophosphate / analogs & derivatives*
  • Adenosine Monophosphate / chemistry
  • Adenosine Monophosphate / pharmacology
  • Alanine / analogs & derivatives*
  • Alanine / chemistry
  • Alanine / pharmacology
  • Animals
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Coronavirus / enzymology
  • Ebolavirus / enzymology
  • Gene Expression
  • Middle East Respiratory Syndrome Coronavirus / enzymology*
  • Nucleic Acid Synthesis Inhibitors / chemistry
  • Nucleic Acid Synthesis Inhibitors / pharmacology*
  • RNA
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors*
  • RNA-Dependent RNA Polymerase / genetics
  • Sf9 Cells
  • Viral Nonstructural Proteins / genetics
  • Virus Replication / drug effects*


  • Antiviral Agents
  • Nucleic Acid Synthesis Inhibitors
  • RNA primers
  • Viral Nonstructural Proteins
  • remdesivir
  • Adenosine Monophosphate
  • RNA
  • RNA-Dependent RNA Polymerase
  • Alanine

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