Disulfiram can inhibit MERS and SARS coronavirus papain-like proteases via different modes

Antiviral Res. 2018 Feb;150:155-163. doi: 10.1016/j.antiviral.2017.12.015. Epub 2017 Dec 28.

Abstract

Severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in southern China in late 2002 and caused a global outbreak with a fatality rate around 10% in 2003. Ten years later, a second highly pathogenic human CoV, MERS-CoV, emerged in the Middle East and has spread to other countries in Europe, North Africa, North America and Asia. As of November 2017, MERS-CoV had infected at least 2102 people with a fatality rate of about 35% globally, and hence there is an urgent need to identify antiviral drugs that are active against MERS-CoV. Here we show that a clinically available alcohol-aversive drug, disulfiram, can inhibit the papain-like proteases (PLpros) of MERS-CoV and SARS-CoV. Our findings suggest that disulfiram acts as an allosteric inhibitor of MERS-CoV PLpro but as a competitive (or mixed) inhibitor of SARS-CoV PLpro. The phenomenon of slow-binding inhibition and the irrecoverability of enzyme activity after removing unbound disulfiram indicate covalent inactivation of SARS-CoV PLpro by disulfiram, while synergistic inhibition of MERS-CoV PLpro by disulfiram and 6-thioguanine or mycophenolic acid implies the potential for combination treatments using these three clinically available drugs.

Keywords: 6-Thioguanine; Disulfiram; MERS- and SARS-CoV; Mycophenolic acid; Papain-like protease; Synergistic inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology*
  • Disulfiram / chemistry
  • Disulfiram / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Humans
  • Inhibitory Concentration 50
  • Microbial Sensitivity Tests
  • Middle East Respiratory Syndrome Coronavirus / drug effects*
  • Middle East Respiratory Syndrome Coronavirus / enzymology*
  • Middle East Respiratory Syndrome Coronavirus / genetics
  • Models, Molecular
  • Molecular Conformation
  • Peptide Hydrolases / chemistry
  • Peptide Hydrolases / genetics
  • Peptide Hydrolases / metabolism*
  • Protein Binding
  • SARS Virus / drug effects*
  • SARS Virus / enzymology*
  • SARS Virus / genetics

Substances

  • Antiviral Agents
  • Peptide Hydrolases
  • Disulfiram