書誌事項
- 公開日
- 2021-08-11
- 権利情報
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- https://creativecommons.org/licenses/by/4.0
- https://creativecommons.org/licenses/by/4.0
- DOI
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- 10.1038/s41594-021-00651-0
- 公開者
- Springer Science and Business Media LLC
この論文をさがす
説明
<jats:title>Abstract</jats:title> <jats:p> 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, β- <jats:sc>d</jats:sc> - <jats:italic>N</jats:italic> <jats:sup>4</jats:sup> -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. </jats:p>
収録刊行物
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- Nature Structural & Molecular Biology
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Nature Structural & Molecular Biology 28 (9), 740-746, 2021-08-11
Springer Science and Business Media LLC