Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of COVID-19, uses an RNA-dependent RNA polymerase (RdRp) for the replication of its genome and the transcription of its genes. We found that the catalytic subunit of the RdRp, nsp12, ligates two iron-sulfur metal cofactors in sites that were modeled as zinc centers in the available cryo-electron microscopy structures of the RdRp complex. These metal binding sites are essential for replication and for interaction with the viral helicase. Oxidation of the clusters by the stable nitroxide TEMPOL caused their disassembly, potently inhibited the RdRp, and blocked SARS-CoV-2 replication in cell culture. These iron-sulfur clusters thus serve as cofactors for the SARS-CoV-2 RdRp and are targets for therapy of COVID-19.
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
MeSH terms
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Amino Acid Motifs
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Animals
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Antiviral Agents / pharmacology
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Binding Sites
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Catalytic Domain
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Chlorocebus aethiops
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Coenzymes / chemistry
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Coenzymes / metabolism*
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Coronavirus RNA-Dependent RNA Polymerase / antagonists & inhibitors*
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Coronavirus RNA-Dependent RNA Polymerase / chemistry*
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Coronavirus RNA-Dependent RNA Polymerase / metabolism
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Cyclic N-Oxides / pharmacology*
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Enzyme Inhibitors / pharmacology
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Iron / chemistry
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Iron / metabolism*
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Protein Domains
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RNA Helicases / metabolism
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SARS-CoV-2 / drug effects*
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SARS-CoV-2 / enzymology
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SARS-CoV-2 / physiology
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Spin Labels
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Sulfur / chemistry
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Sulfur / metabolism*
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Vero Cells
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Viral Nonstructural Proteins / metabolism
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Virus Replication / drug effects
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Zinc / metabolism
Substances
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Antiviral Agents
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Coenzymes
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Cyclic N-Oxides
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Enzyme Inhibitors
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Spin Labels
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Viral Nonstructural Proteins
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Sulfur
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Iron
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Coronavirus RNA-Dependent RNA Polymerase
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NSP12 protein, SARS-CoV-2
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RNA Helicases
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Zinc
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tempol