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

doi:10.1126/science.abi5224

GSTDTAP > 气候变化

DOI	10.1126/science.abi5224
	Fe-S cofactors in the SARS-CoV-2 RNA-dependent RNA polymerase are potential antiviral targets
	Nunziata Maio; Bernard A. P. Lafont; Debangsu Sil; Yan Li; J. Martin Bollinger; Carsten Krebs; Theodore C. Pierson; W. Marston Linehan; Tracey A. Rouault
	2021-07-09
发表期刊	Science
出版年	2021
英文摘要	Iron–sulfur clusters are important cofactors for proteins involved in metabolism and electron transfer but are also sometimes found in enzymes involved in transcription and replication of DNA. In vitro expression of such enzymes can result in faulty cluster assembly and confusion about the composition of the functional enzyme. Using a careful anoxic purification scheme, Maio et al. found that the severe acute respiratory syndrome coronavirus 2 RNA–dependent RNA polymerase contains two iron–sulfur clusters at two sites previously observed to bind zinc ions. Mutation of the ligating cysteine residues resulted in loss of polymerase activity. A less severe loss of activity was seen in the zinc-containing enzyme. Treatment with the nitroxide drug TEMPOL resulted in degradation of the clusters, enzyme inhibition, and inhibition of viral replication in cell culture. Science , abi5224, this issue p. [236][1] 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. [1]: /lookup/doi/10.1126/science.abi5224
领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/334287
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Nunziata Maio,Bernard A. P. Lafont,Debangsu Sil,et al. Fe-S cofactors in the SARS-CoV-2 RNA-dependent RNA polymerase are potential antiviral targets[J]. Science,2021.
APA	Nunziata Maio.,Bernard A. P. Lafont.,Debangsu Sil.,Yan Li.,J. Martin Bollinger.,...&Tracey A. Rouault.(2021).Fe-S cofactors in the SARS-CoV-2 RNA-dependent RNA polymerase are potential antiviral targets.Science.
MLA	Nunziata Maio,et al."Fe-S cofactors in the SARS-CoV-2 RNA-dependent RNA polymerase are potential antiviral targets".Science (2021).