Tags

Type your tag names separated by a space and hit enter

Fe-S cofactors in the SARS-CoV-2 RNA-dependent RNA polymerase are potential antiviral targets.
Science. 2021 07 09; 373(6551):236-241.Sci

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+Show Affiliations

Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.SARS-CoV-2 Virology Core, Laboratory of Viral Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA.Proteomics Core Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA. Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA.Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA. Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA.Laboratory of Viral Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. rouault@mail.nih.gov.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural

Language

eng

PubMed ID

34083449

Citation

Maio, Nunziata, et al. "Fe-S Cofactors in the SARS-CoV-2 RNA-dependent RNA Polymerase Are Potential Antiviral Targets." Science (New York, N.Y.), vol. 373, no. 6551, 2021, pp. 236-241.
Maio N, Lafont BAP, Sil D, et al. Fe-S cofactors in the SARS-CoV-2 RNA-dependent RNA polymerase are potential antiviral targets. Science. 2021;373(6551):236-241.
Maio, N., Lafont, B. A. P., Sil, D., Li, Y., Bollinger, J. M., Krebs, C., Pierson, T. C., Linehan, W. M., & Rouault, T. A. (2021). Fe-S cofactors in the SARS-CoV-2 RNA-dependent RNA polymerase are potential antiviral targets. Science (New York, N.Y.), 373(6551), 236-241. https://doi.org/10.1126/science.abi5224
Maio N, et al. Fe-S Cofactors in the SARS-CoV-2 RNA-dependent RNA Polymerase Are Potential Antiviral Targets. Science. 2021 07 9;373(6551):236-241. PubMed PMID: 34083449.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fe-S cofactors in the SARS-CoV-2 RNA-dependent RNA polymerase are potential antiviral targets. AU - Maio,Nunziata, AU - Lafont,Bernard A P, AU - Sil,Debangsu, AU - Li,Yan, AU - Bollinger,J Martin,Jr AU - Krebs,Carsten, AU - Pierson,Theodore C, AU - Linehan,W Marston, AU - Rouault,Tracey A, Y1 - 2021/06/03/ PY - 2021/03/20/received PY - 2021/05/28/accepted PY - 2021/6/5/pubmed PY - 2021/7/23/medline PY - 2021/6/4/entrez SP - 236 EP - 241 JF - Science (New York, N.Y.) JO - Science VL - 373 IS - 6551 N2 - 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. SN - 1095-9203 UR - https://www.unboundmedicine.com/medline/citation/34083449/Fe-S_cofactors_in_the_SARS-CoV-2_RNA-dependent_RNA_polymerase_are_potential_antiviral_targets. L2 - https://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=34083449 DB - PRIME DP - Unbound Medicine ER -