Inhibition of proprotein convertases abrogates processing of the middle eastern respiratory syndrome coronavirus spike protein in infected cells but does not reduce viral infectivity

J Infect Dis. 2015 Mar 15;211(6):889-97. doi: 10.1093/infdis/jiu407. Epub 2014 Jul 23.


Middle East respiratory syndrome coronavirus (MERS-CoV) infection is associated with a high case-fatality rate, and the potential pandemic spread of the virus is a public health concern. The spike protein of MERS-CoV (MERS-S) facilitates viral entry into host cells, which depends on activation of MERS-S by cellular proteases. Proteolytic activation of MERS-S during viral uptake into target cells has been demonstrated. However, it is unclear whether MERS-S is also cleaved during S protein synthesis in infected cells and whether cleavage is required for MERS-CoV infectivity. Here, we show that MERS-S is processed by proprotein convertases in MERS-S-transfected and MERS-CoV-infected cells and that several RXXR motifs located at the border between the surface and transmembrane subunit of MERS-S are required for efficient proteolysis. However, blockade of proprotein convertases did not impact MERS-S-dependent transduction of target cells expressing high amounts of the viral receptor, DPP4, and did not modulate MERS-CoV infectivity. These results show that MERS-S is a substrate for proprotein convertases and demonstrate that processing by these enzymes is dispensable for S protein activation. Efforts to inhibit MERS-CoV infection by targeting host cell proteases should therefore focus on enzymes that process MERS-S during viral uptake into target cells.

Keywords: MERS-coronavirus; TMPRSS2; activation; proprotein convertase; protease; spike; trypsin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antiviral Agents / pharmacology
  • Coronavirus / physiology*
  • Drug Evaluation, Preclinical
  • HEK293 Cells
  • Humans
  • Molecular Sequence Data
  • Proprotein Convertases / antagonists & inhibitors*
  • Protease Inhibitors / pharmacology
  • Protein Processing, Post-Translational
  • Proteolysis
  • Spike Glycoprotein, Coronavirus / chemistry
  • Spike Glycoprotein, Coronavirus / metabolism*
  • Virus Internalization


  • Antiviral Agents
  • Protease Inhibitors
  • Spike Glycoprotein, Coronavirus
  • Proprotein Convertases