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10.1038/s41594-021-00651-0 http://scihub22266oqcxt.onion/10.1038/s41594-021-00651-0 34381216!8437801!34381216     free     free     free Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       Nat+Struct+Mol+Biol 2021 ; 28 (9): 740-746 Nephropedia Template TP {{tp|p=34381216|t=2021. Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis |pdf=|usr=}}{{34381216}} gab.com Text Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis JO: Nat Struct Mol Biol http://www.kidney.de/pget.php?&tw=1&pmid=34381216 #FOAvip 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. Twit Text FOAVip Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis ????Nat Struct Mol Biol http://www.kidney.de/pget.php?&tw=1&pmid=34381216 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=34381216 #FOAvip English Wikipedia <ref>{{Cite pmid|34381216}}</ref> Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis #MMPMID34381216 Kabinger F; Stiller C; Schmitzova J; Dienemann C; Kokic G; Hillen HS; Hobartner C; Cramer P Nat Struct Mol Biol 2021[Sep]; 28 (9): 740-746 PMID34381216show ga 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. |Animals[MESH] |Antiviral Agents/chemistry/metabolism/pharmacology[MESH] |Base Sequence[MESH] |COVID-19 Drug Treatment[MESH] |COVID-19/*prevention & control/virology[MESH] |Cytidine/*analogs & derivatives/chemistry/metabolism/pharmacology[MESH] |Humans[MESH] |Hydroxylamines/chemistry/*metabolism/pharmacology[MESH] |Models, Molecular[MESH] |Molecular Structure[MESH] |Mutagenesis/drug effects/*genetics[MESH] |Mutation/drug effects/genetics[MESH] |Nucleic Acid Conformation[MESH] |Protein Binding/drug effects[MESH] |Protein Conformation[MESH] |RNA, Viral/chemistry/*genetics/metabolism[MESH] |RNA-Dependent RNA Polymerase/chemistry/genetics/metabolism[MESH] |SARS-CoV-2/drug effects/*genetics/physiology[MESH]Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis (epmc).pdf DeepDyve Pubget Overpricing