Molnupiravir, a prodrug of the nucleoside derivative β-D-N-hydroxycytidine (NHC), is currently in clinical trials for COVID-19 therapy. However, the biochemical mechanisms involved in molnupiravir-induced mutagenesis had not been explored. In a recent study, Gordon et al. demonstrated that NHC can be incorporated into viral RNA and subsequently extended and used as template for RNA-dependent RNA synthesis, proposing a mutagenesis model consistent with available virological evidence. Their study uncovers molecular mechanisms by which molnupiravir drives SARS-CoV-2 into error catastrophe.
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| http://dx.doi.org/10.1016/j.jbc.2021.100867 | DOI Listing |
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Molecular Immunity Unit, University of Cambridge Department of Medicine, Medical Research Council-Laboratory of Molecular Biology, Cambridge, UK.
Molnupiravir, an antiviral medication widely used against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), acts by inducing mutations in the virus genome during replication. Most random mutations are likely to be deleterious to the virus and many will be lethal; thus, molnupiravir-induced elevated mutation rates reduce viral load. However, if some patients treated with molnupiravir do not fully clear the SARS-CoV-2 infections, there could be the potential for onward transmission of molnupiravir-mutated viruses.
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Nat Struct Mol Biol
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Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology, Göttingen, Germany.
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).
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J Biol Chem
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Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid, Madrid, Spain. Electronic address:
Molnupiravir, a prodrug of the nucleoside derivative β-D-N-hydroxycytidine (NHC), is currently in clinical trials for COVID-19 therapy. However, the biochemical mechanisms involved in molnupiravir-induced mutagenesis had not been explored. In a recent study, Gordon et al.
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J Biol Chem
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Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada; Li Ka Shing Institute of Virology at University of Alberta, Edmonton, Alberta, Canada. Electronic address:
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-N-hydroxycytidine (NHC). Molnupiravir or NHC can increase G to A and C to U transition mutations in replicating coronaviruses.
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