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

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.

Automated summary

Research has shown that the catalytic subunit nsp12 of the SARS-CoV-2 RdRp complex ligates two iron-sulfur metal cofactors which are essential for viral replication and interaction with the viral helicase. Oxidation of these clusters by TEMPOL inhibits RdRp activity and blocks SARS-CoV-2 replication in cell culture, indicating that these iron-sulfur clusters could be targeted for therapy of COVID-19.