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Molnupiravir promotes SARS-CoV-2 mutagenesis via the RNA template

The Journal of biological chemistry, 2021-07, Vol.297 (1), p.100770-100770, Article 100770 [Peer Reviewed Journal]

2021 The Authors ;Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved. ;2021 The Authors 2021 ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1016/j.jbc.2021.100770 ;PMID: 33989635

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  • Title:
    Molnupiravir promotes SARS-CoV-2 mutagenesis via the RNA template
  • Author: Gordon, Calvin J. ; Tchesnokov, Egor P. ; Schinazi, Raymond F. ; Götte, Matthias
  • Subjects: Accelerated Communication ; antiviral agent ; coronavirus ; Covid-19 ; drug development ; mutagen ; nucleoside analogue ; RNA-dependent RNA polymerase ; SARS-CoV-2
  • Is Part Of: The Journal of biological chemistry, 2021-07, Vol.297 (1), p.100770-100770, Article 100770
  • Description: 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 β-D-N4-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.
  • Publisher: United States: Elsevier Inc
  • Language: English
  • Identifier: ISSN: 0021-9258
    EISSN: 1083-351X
    DOI: 10.1016/j.jbc.2021.100770
    PMID: 33989635
  • Source: PubMed Central
    Alma/SFX Local Collection
    DOAJ Directory of Open Access Journals
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