期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 28, 期 9, 页码 740-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41594-021-00651-0
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资金
- Deutsche Forschungsgemeinschaft [SFB1190, FOR2848, EXC 2067/1-390729940, SFB860, SPP2191]
- DFG [SPP1784]
- ERC Consolidator Grant illumizymes [682586]
- ERC Advanced Investigator Grant CHROMATRANS [693023]
- European Research Council (ERC) [682586, 693023] Funding Source: European Research Council (ERC)
Molnupiravir is an oral antiviral drug candidate that increases viral RNA mutations frequency and inhibits replication of SARS-CoV-2 by altering the substrate preference of RdRp. This two-step mutagenesis mechanism can explain the broad-spectrum antiviral activity of molnupiravir, making it a promising COVID-19 treatment option.
Molnupiravir is an orally available antiviral drug candidate currently in phase III trials for the treatment of patients with COVID-19. Molnupiravir increases the frequency of viral RNA mutations and impairs SARS-CoV-2 replication in animal models and in humans. Here, we establish the molecular mechanisms underlying molnupiravir-induced RNA mutagenesis by the viral RNA-dependent RNA polymerase (RdRp). Biochemical assays show that the RdRp uses the active form of molnupiravir, beta-d-N-4-hydroxycytidine (NHC) triphosphate, as a substrate instead of cytidine triphosphate or uridine triphosphate. When the RdRp uses the resulting RNA as a template, NHC directs incorporation of either G or A, leading to mutated RNA products. Structural analysis of RdRp-RNA complexes that contain mutagenesis products shows that NHC can form stable base pairs with either G or A in the RdRp active center, explaining how the polymerase escapes proofreading and synthesizes mutated RNA. This two-step mutagenesis mechanism probably applies to various viral polymerases and can explain the broad-spectrum antiviral activity of molnupiravir. Quantitative biochemical assays and high-resolution cryo-EM analysis reveal how the COVID-19 antiviral drug candidate molnupiravir causes lethal viral mutagenesis by the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2.
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