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

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (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.

Combinations of drugs might increase the survival chances of COVID-19 patients: Literature review till date

“…Periodontitis and associated bacterial can drive inflammation in COVID-19 patients [96,97,112]. 7. Periodontitis and associated bacterial LPS can bind to SARS-COV-2 [834] and induces elevated proinflammatory immune responses.…”

Walking around Ribosomal Small Subunit: A Possible “Tourist Map” for Electron Holes

“…We expect that this fluorescence will be quenched when the cluster becomes reduced (i.e., hole leaves it and reaches the localization site). Interestingly, very recently, it was observed that in a rather different system-RNAdependent RNA polymerase of the SARS-CoV-2 coronavirus, the culprit of continuing COVID-19 pandemic-two Fe 4 S 4 clusters are incorporated [49]. The role of these clusters is not clear, but it was shown that their degradation inhibits virus replication [49].…”

“…Interestingly, very recently, it was observed that in a rather different system-RNAdependent RNA polymerase of the SARS-CoV-2 coronavirus, the culprit of continuing COVID-19 pandemic-two Fe 4 S 4 clusters are incorporated [49]. The role of these clusters is not clear, but it was shown that their degradation inhibits virus replication [49]. We suggest that these clusters could provide/accept charge carriers and enable signaling between the proteins involved into RNA replication like it was observed for DNA [18,22] and proposed for ribosome [14].…”

The Interaction of Water-Soluble Nitroxide Radicals with Photosystem II

“…Water-soluble nitroxide radicals have found numerous applications in chemistry, biology, and medicine. The most interesting applications of nitroxide radicals in biology and medicine are associated with the development of drugs [1]. For example, recently the stable nitroxide 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) has been suggested as the reagent that can cause the oxidation of the Fe-S clusters of the RNA-dependent RNA polymerase (RdRp).…”

“…Figure5highlights the suitable positions of the spin labels used in this work that can be clustered on the PS II surface in the close vicinity of the redox group of PQ A (sites 1 and 2) and the binding sites in the PQ B -binding pocket in PS II (site 3)1 . The colored balls designate the selected positions of different spin labels determined by the docking method.…”