Structure of the SARS-CoV-2 RNA-dependent RNA polymerase in the presence of favipiravir-RTP.
Katerina Naydenova,Kyle W. Muir,Long-Fei Wu,Ziguo Zhang,Francesca Coscia,M. J. Peet,Pablo Castro-Hartmann,Pu Qian,Kasim Sader,Kyle Dent,Dari Kimanius,John D. Sutherland,Jan Löwe,David Barford,Christopher J. Russo +14 more
TLDR
In this article, the structure of the RNA polymerase inhibitor favipiravir ribonucleoside triphosphate (favipirusavir-RTP) in complex with the SARS-CoV-2 RNA-dependent RNA polymerases (RdRp) bound to a template: primer RNA duplex, determined by electron cryomicroscopy (cryoEM) to a resolution of 25 A.Abstract:
The RNA polymerase inhibitor favipiravir is currently in clinical trials as a treatment for infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), despite limited information about the molecular basis for its activity Here we report the structure of favipiravir ribonucleoside triphosphate (favipiravir-RTP) in complex with the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) bound to a template:primer RNA duplex, determined by electron cryomicroscopy (cryoEM) to a resolution of 25 A The structure shows clear evidence for the inhibitor at the catalytic site of the enzyme, and resolves the conformation of key side chains and ions surrounding the binding pocket Polymerase activity assays indicate that the inhibitor is weakly incorporated into the RNA primer strand, and suppresses RNA replication in the presence of natural nucleotides The structure reveals an unusual, nonproductive binding mode of favipiravir-RTP at the catalytic site of SARS-CoV-2 RdRp, which explains its low rate of incorporation into the RNA primer strand Together, these findings inform current and future efforts to develop polymerase inhibitors for SARS coronavirusesread more
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Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis.
Florian Kabinger,Carina Stiller,Jana Schmitzová,Christian Dienemann,Goran Kokic,Hauke S. Hillen,Hauke S. Hillen,Claudia Höbartner,Patrick Cramer +8 more
TL;DR: In this paper, the active form of molnupiravir, β-D-N4-hydroxycytidine (NHC) triphosphate, was used as a substrate instead of cytidine triphophosphate or uridine tri phosphate.
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SARS-CoV-2: from its discovery to genome structure, transcription, and replication
TL;DR: SARS-CoV-2 is an extremely contagious respiratory virus causing adult atypical pneumonia COVID-19 with severe acute respiratory syndrome (SARS) as discussed by the authors, which has a single-stranded, positive-sense RNA (+RNA) genome of 29.9 kb and exhibits significant genetic shift from different isolates.
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Structure genomics of SARS-CoV-2 and its Omicron variant: drug design templates for COVID-19
TL;DR: In this article , the authors summarize the structural biology of SARS-CoV-2 and discuss important biological issues that remain to be addressed, highlighting the importance of structure in drug discovery to combat COVID-19.
Journal ArticleDOI
Structure and function of SARS-CoV-2 polymerase.
TL;DR: An overview of the currently available coronavirus RNA polymerase structures and functional studies can be found in this paper, where the authors provide a molecular understanding of the viral polymerase, its interactions with accessory factors, and the mechanisms by which promising antivirus drugs may inhibit the virus replication.
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Molnupiravir: A lethal mutagenic drug against rapidly mutating severe acute respiratory syndrome coronavirus 2—A narrative review
Sri Masyeni,Muhammad Iqhrammullah,Andri Frediansyah,Firzan Nainu,Trina Ekawati Tallei,Talha Bin Emran,Youdiil Ophinni,Kuldeep Dhama,Harapan Harapan +8 more
TL;DR: With its administration via the oral route, molnupiravir is expected to turn the tide of the COVID‐19 pandemic and be a key therapeutic strategy in the ongoing coronavirus disease 2019 pandemic.
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TL;DR: These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay.
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