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

• Published in: Antiviral research 2018-02, Vol.150, p.155-163
• Main Authors: Lin, Min-Han, Moses, David C., Hsieh, Chih-Hua, Cheng, Shu-Chun, Chen, Yau-Hung, Sun, Chiao-Yin, Chou, Chi-Yuan
• Format: Article
• Language: English
• Subjects: 6-Thioguanine; Antiviral Agents - pharmacology; Disulfiram; Disulfiram - chemistry; Disulfiram - pharmacology; Dose-Response Relationship, Drug; Enzyme Activation - drug effects; Humans; Inhibitory Concentration 50; MERS- and SARS-CoV; 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; Mycophenolic acid; Papain-like protease; Peptide Hydrolases - chemistry; Peptide Hydrolases - genetics; Peptide Hydrolases - metabolism; Protein Binding; SARS Virus - drug effects; SARS Virus - enzymology; SARS Virus - genetics; Synergistic inhibition
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2017.12.015

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. •Disulfiram, a drug for use in alcohol aversion therapy, can inhibit the papain-like proteases of MERS-CoV and SARS-CoV.•Disulfiram is a noncompetitive inhibitor of MERS-CoV papain-like protease.•Disulfiram, 6-thioguanine and mycophenolic acid can synergistically inhibit MERS-CoV papain-like protease.•Disulfiram is a competitive inhibitor of SARS-CoV papain-like protease.•Disulfiram is a slow-binding inhibitor that forms a covalent adduct at the active site of SARS-CoV papain-like protease.