Fe-S cofactors in the SARS-CoV-2 RNA-dependent RNA polymerase are potential antiviral targets.

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.

• Authors: Nunziata Maio, Bernard A P Lafont, Debangsu Sil, Yan Li, J Martin Bollinger Jr, Carsten Krebs, Theodore C Pierson, W Marston Linehan, Tracey A Rouault
• Journal: Science (New York, N.Y.) (Science) Vol. 373 Issue 6551 Pg. 236-241 (07 09 2021) ISSN: 1095-9203 [Electronic] United States
• PMID: 34083449 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
• Copyright: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Antiviral Agents
• Coenzymes
• Cyclic N-Oxides
• Enzyme Inhibitors
• Spin Labels
• Viral Nonstructural Proteins
• Sulfur
• Iron
• Coronavirus RNA-Dependent RNA Polymerase
• NSP12 protein, SARS-CoV-2
• RNA Helicases
• Zinc
• tempol

Topics

• Amino Acid Motifs
• Animals
• Antiviral Agents (pharmacology)
• Binding Sites
• Catalytic Domain
• Chlorocebus aethiops
• Coenzymes (chemistry, metabolism)
• Coronavirus RNA-Dependent RNA Polymerase (antagonists & inhibitors, chemistry, metabolism)
• Cyclic N-Oxides (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Iron (chemistry, metabolism)
• Protein Domains
• RNA Helicases (metabolism)
• SARS-CoV-2 (drug effects, enzymology, physiology)
• Spin Labels
• Sulfur (chemistry, metabolism)
• Vero Cells
• Viral Nonstructural Proteins (metabolism)
• Virus Replication (drug effects)
• Zinc (metabolism)