Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus

Antiviral Res. 2015 Mar;115:9-16. doi: 10.1016/j.antiviral.2014.12.011. Epub 2014 Dec 24.

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) is a new highly pathogenic human coronaviruses that emerged in Jeddah and Saudi Arabia and has quickly spread to other countries in Middle East, Europe and North Africa since 2012. Up to 17 December 2014, it has infected at least 938 people with a fatality rate of about 36% globally. This has resulted in an urgent need to identify antiviral drugs that are active against MERS-CoV. The papain-like protease (PL(pro)) of MERS-CoV represents an important antiviral target as it is not only essential for viral maturation, but also antagonizes interferon stimulation of the host via its deubiquitination activity. Here, we report the discovery that two SARS-CoV PL(pro) inhibitors, 6-mercaptopurine (6MP) and 6-thioguanine (6TG), as well as the immunosuppressive drug mycophenolic acid, are able to inhibit MERS-CoV PL(pro). Their inhibition mechanisms and mutually binding synergistic effect were also investigated. Our results identify for the first time three inhibitors targeting MERS-CoV PL(pro) and these can now be used as lead compounds for further antiviral drug development.

Keywords: 6-Mercaptopurine; 6-Thioguanine; MERS-CoV papain-like protease; Mycophenolic acid; Synergistic inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology*
  • Cysteine Endopeptidases
  • Cysteine Proteases / chemistry
  • Cysteine Proteases / metabolism*
  • Cysteine Proteinase Inhibitors / pharmacology*
  • Drug Synergism
  • Mercaptopurine / pharmacology*
  • Middle East Respiratory Syndrome Coronavirus / drug effects*
  • Middle East Respiratory Syndrome Coronavirus / enzymology
  • Models, Molecular
  • Mycophenolic Acid / pharmacology*
  • SARS Virus / drug effects
  • SARS Virus / enzymology
  • Thioguanine / pharmacology*
  • Viral Proteins / antagonists & inhibitors

Substances

  • Antiviral Agents
  • Cysteine Proteinase Inhibitors
  • Viral Proteins
  • Mercaptopurine
  • Cysteine Proteases
  • 3C-like proteinase, Coronavirus
  • Cysteine Endopeptidases
  • Thioguanine
  • Mycophenolic Acid