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，它使用一种依赖于 RNA 的 RNA 聚合酶 (RdRp) 来复制其基因组和转录其基因。我们发现 RdRp 的催化亚基 nsp12 在 RdRp 复合物的可用低温电子显微镜结构中被模拟为锌中心的位点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是必不可少的。稳定的氮氧化物 TEMPOL 对簇的氧化导致它们的分解，有效地抑制了 RdRp，并阻止了 SARS-CoV-2 在细胞培养物中的复制。因此，这些铁硫簇可作为 SARS-CoV-2 RdRp 的辅助因子，并且是 COVID-19 治疗的靶点。