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

Identifieur interne : 000A12 ( PubMed/Checkpoint ); précédent : 000A11; suivant : 000A13

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

Auteurs : Min-Han Lin [Taïwan] ; David C. Moses [Taïwan] ; Chih-Hua Hsieh [Taïwan] ; Shu-Chun Cheng [Taïwan] ; Yau-Hung Chen [Taïwan] ; Chiao-Yin Sun [Taïwan] ; Chi-Yuan Chou [Taïwan]

Source :

Antiviral research [ 1872-9096 ] ; 2018.

RBID : pubmed:29289665

Descripteurs français

English descriptors

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

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.

DOI: 10.1016/j.antiviral.2017.12.015
PubMed: 29289665

Affiliations:

Taïwan

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<front><div type="abstract" xml:lang="en">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<sup>pro</sup>
s) of MERS-CoV and SARS-CoV. Our findings suggest that disulfiram acts as an allosteric inhibitor of MERS-CoV PL<sup>pro</sup>
 but as a competitive (or mixed) inhibitor of SARS-CoV PL<sup>pro</sup>
. The phenomenon of slow-binding inhibition and the irrecoverability of enzyme activity after removing unbound disulfiram indicate covalent inactivation of SARS-CoV PL<sup>pro</sup>
 by disulfiram, while synergistic inhibition of MERS-CoV PL<sup>pro</sup>
 by disulfiram and 6-thioguanine or mycophenolic acid implies the potential for combination treatments using these three clinically available drugs.</div>
</front>
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<Abstract><AbstractText>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<sup>pro</sup>
s) of MERS-CoV and SARS-CoV. Our findings suggest that disulfiram acts as an allosteric inhibitor of MERS-CoV PL<sup>pro</sup>
 but as a competitive (or mixed) inhibitor of SARS-CoV PL<sup>pro</sup>
. The phenomenon of slow-binding inhibition and the irrecoverability of enzyme activity after removing unbound disulfiram indicate covalent inactivation of SARS-CoV PL<sup>pro</sup>
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Disulfiram can inhibit MERS and SARS coronavirus papain-like proteases via different modes.

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

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