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Fe-S cofactors in the SARS-CoV-2 RNA-dependent RNA polymerase are potential antiviral targets.
Maio, Nunziata; Lafont, Bernard A P; Sil, Debangsu; Li, Yan; Bollinger, J Martin; Krebs, Carsten; Pierson, Theodore C; Linehan, W Marston; Rouault, Tracey A.
  • Maio N; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
  • Lafont BAP; 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.
  • Sil D; Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA.
  • Li Y; Proteomics Core Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
  • Bollinger JM; Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA.
  • Krebs C; Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA.
  • Pierson TC; Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA.
  • Linehan WM; Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA.
  • Rouault TA; Laboratory of Viral Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Science ; 373(6551): 236-241, 2021 07 09.
Article in English | MEDLINE | ID: covidwho-1266364
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Sulfur / Coenzymes / Cyclic N-Oxides / Coronavirus RNA-Dependent RNA Polymerase / SARS-CoV-2 / Iron Limits: Animals Language: English Journal: Science Year: 2021 Document Type: Article Affiliation country: Science.abi5224

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Sulfur / Coenzymes / Cyclic N-Oxides / Coronavirus RNA-Dependent RNA Polymerase / SARS-CoV-2 / Iron Limits: Animals Language: English Journal: Science Year: 2021 Document Type: Article Affiliation country: Science.abi5224