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

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 (PL ^pros) of MERS-CoV and SARS-CoV. Our findings suggest that disulfiram acts as an allosteric inhibitor of MERS-CoV PL ^pro but as a competitive (or mixed) inhibitor of SARS-CoV PL ^pro. The phenomenon of slow-binding inhibition and the irrecoverability of enzyme activity after removing unbound disulfiram indicate covalent inactivation of SARS-CoV PL ^pro by disulfiram, while synergistic inhibition of MERS-CoV PL ^pro by disulfiram and 6-thioguanine or mycophenolic acid implies the potential for combination treatments using these three clinically available drugs.

Highlights

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  Disulfiram, a drug for use in alcohol aversion therapy, can inhibit the papain-like proteases of MERS-CoV and SARS-CoV.

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  Disulfiram is a noncompetitive inhibitor of MERS-CoV papain-like protease.

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  Disulfiram, 6-thioguanine and mycophenolic acid can synergistically inhibit MERS-CoV papain-like protease.

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  Disulfiram is a competitive inhibitor of SARS-CoV papain-like protease.

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  Disulfiram is a slow-binding inhibitor that forms a covalent adduct at the active site of SARS-CoV papain-like protease.