期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-020-20542-0
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资金
- Deutsche Forschungsgemeinschaft [FOR2848, SFB860, SPP2191, EXC 2067/1-390729940]
- DFG [SPP1784]
- ERC Consolidator Grant illumizymes [682586]
- ERC Advanced Investigator Grant CHROMATRANS [693023]
- European Research Council (ERC) [693023, 682586] Funding Source: European Research Council (ERC)
Remdesivir is the only FDA-approved drug for treating COVID-19 patients, working by inhibiting the RNA-dependent RNA polymerase (RdRp) of coronaviruses. It hinders RNA synthesis and impairs proofreading by the viral 3'-exonuclease, leading to a stalled replication process.
Remdesivir is the only FDA-approved drug for the treatment of COVID-19 patients. The active form of remdesivir acts as a nucleoside analog and inhibits the RNA-dependent RNA polymerase (RdRp) of coronaviruses including SARS-CoV-2. Remdesivir is incorporated by the RdRp into the growing RNA product and allows for addition of three more nucleotides before RNA synthesis stalls. Here we use synthetic RNA chemistry, biochemistry and cryo-electron microscopy to establish the molecular mechanism of remdesivir-induced RdRp stalling. We show that addition of the fourth nucleotide following remdesivir incorporation into the RNA product is impaired by a barrier to further RNA translocation. This translocation barrier causes retention of the RNA 3'-nucleotide in the substrate-binding site of the RdRp and interferes with entry of the next nucleoside triphosphate, thereby stalling RdRp. In the structure of the remdesivir-stalled state, the 3'-nucleotide of the RNA product is matched and located with the template base in the active center, and this may impair proofreading by the viral 3'-exonuclease. These mechanistic insights should facilitate the quest for improved antivirals that target coronavirus replication.
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