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10.1016/j.jbc.2021.100770 http://scihub22266oqcxt.onion/10.1016/j.jbc.2021.100770 33989635!8110631!33989635     free     free     free Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       J+Biol+Chem 2021 ; 297 (1): 100770 Nephropedia Template TP {{tp|p=33989635|t=2021. Molnupiravir promotes SARS-CoV-2 mutagenesis via the RNA template |pdf=|usr=}}{{33989635}} gab.com Text Molnupiravir promotes SARS-CoV-2 mutagenesis via the RNA template JO: J Biol Chem http://www.kidney.de/pget.php?&tw=1&pmid=33989635 #FOAvip The RNA-dependent RNA polymerase of the severe acute respiratory syndrome coronavirus 2 is an important target in current drug development efforts for the treatment of coronavirus disease 2019. Molnupiravir is a broad-spectrum antiviral that is an orally bioavailable prodrug of the nucleoside analogue beta-D-N(4)-hydroxycytidine (NHC). Molnupiravir or NHC can increase G to A and C to U transition mutations in replicating coronaviruses. These increases in mutation frequencies can be linked to increases in antiviral effects; however, biochemical data of molnupiravir-induced mutagenesis have not been reported. Here we studied the effects of the active compound NHC 5'-triphosphate (NHC-TP) against the purified severe acute respiratory syndrome coronavirus 2 RNA-dependent RNA polymerase complex. The efficiency of incorporation of natural nucleotides over the efficiency of incorporation of NHC-TP into model RNA substrates followed the order GTP (12,841) > ATP (424) > UTP (171) > CTP (30), indicating that NHC-TP competes predominantly with CTP for incorporation. No significant inhibition of RNA synthesis was noted as a result of the incorporated monophosphate in the RNA primer strand. When embedded in the template strand, NHC-monophosphate supported the formation of both NHC:G and NHC:A base pairs with similar efficiencies. The extension of the NHC:G product was modestly inhibited, but higher nucleotide concentrations could overcome this blockage. In contrast, the NHC:A base pair led to the observed G to A (G:NHC:A) or C to U (C:G:NHC:A:U) mutations. Together, these biochemical data support a mechanism of action of molnupiravir that is primarily based on RNA mutagenesis mediated via the template strand. Twit Text FOAVip Molnupiravir promotes SARS-CoV-2 mutagenesis via the RNA template ????J Biol Chem http://www.kidney.de/pget.php?&tw=1&pmid=33989635 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=33989635 #FOAvip English Wikipedia <ref>{{Cite pmid|33989635}}</ref> Molnupiravir promotes SARS-CoV-2 mutagenesis via the RNA template #MMPMID33989635 Gordon CJ; Tchesnokov EP; Schinazi RF; Gotte M J Biol Chem 2021[Jul]; 297 (1): 100770 PMID33989635show ga The RNA-dependent RNA polymerase of the severe acute respiratory syndrome coronavirus 2 is an important target in current drug development efforts for the treatment of coronavirus disease 2019. Molnupiravir is a broad-spectrum antiviral that is an orally bioavailable prodrug of the nucleoside analogue beta-D-N(4)-hydroxycytidine (NHC). Molnupiravir or NHC can increase G to A and C to U transition mutations in replicating coronaviruses. These increases in mutation frequencies can be linked to increases in antiviral effects; however, biochemical data of molnupiravir-induced mutagenesis have not been reported. Here we studied the effects of the active compound NHC 5'-triphosphate (NHC-TP) against the purified severe acute respiratory syndrome coronavirus 2 RNA-dependent RNA polymerase complex. The efficiency of incorporation of natural nucleotides over the efficiency of incorporation of NHC-TP into model RNA substrates followed the order GTP (12,841) > ATP (424) > UTP (171) > CTP (30), indicating that NHC-TP competes predominantly with CTP for incorporation. No significant inhibition of RNA synthesis was noted as a result of the incorporated monophosphate in the RNA primer strand. When embedded in the template strand, NHC-monophosphate supported the formation of both NHC:G and NHC:A base pairs with similar efficiencies. The extension of the NHC:G product was modestly inhibited, but higher nucleotide concentrations could overcome this blockage. In contrast, the NHC:A base pair led to the observed G to A (G:NHC:A) or C to U (C:G:NHC:A:U) mutations. Together, these biochemical data support a mechanism of action of molnupiravir that is primarily based on RNA mutagenesis mediated via the template strand. |Antiviral Agents/*pharmacology[MESH] |COVID-19/*virology[MESH] |Cytidine/*analogs & derivatives/pharmacology[MESH] |Humans[MESH] |Hydroxylamines/*pharmacology[MESH] |Mutagenesis[MESH] |Point Mutation/drug effects[MESH] |RNA, Viral/*genetics[MESH]Molnupiravir promotes SARS-CoV-2 mutagenesis via the RNA template (epmc).pdf DeepDyve Pubget Overpricing