SARS-CoV-2 依赖 RNA 的 RNA 聚合酶中的 Fe-S 辅助因子是潜在的抗病毒靶点。

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.

Science. 2021 Jul 9;373(6551):236-241. doi: 10.1126/science.abi5224. Epub 2021 Jun 3.

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.

严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）是 COVID-19 的病原体，它利用 RNA 依赖的 RNA 聚合酶（RdRp）复制其基因组并转录其基因。我们发现，RdRp 的催化亚基 nsp12 在可用于 RdRp 复合物冷冻电镜结构的锌中心模型中连接两个铁硫金属辅因子。这些金属结合位点对于复制和与病毒解旋酶的相互作用至关重要。稳定的氮氧自由基 TEMPOL 对簇的氧化导致它们的解体，强烈抑制 RdRp，并阻断细胞培养中的 SARS-CoV-2 复制。因此，这些铁硫簇是 SARS-CoV-2 RdRp 的辅因子，也是 COVID-19 治疗的靶点。