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

Abstract

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. HighlightsDisulfiram, 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.