Rapid incorporation of Favipiravir by the fast and permissive viral RNA polymerase complex results in SARS-CoV-2 lethal mutagenesis.
Amides
/ pharmacokinetics
Animals
Antiviral Agents
/ pharmacokinetics
Betacoronavirus
/ drug effects
COVID-19
Chlorocebus aethiops
Coronavirus Infections
/ drug therapy
Coronavirus RNA-Dependent RNA Polymerase
Models, Molecular
Mutagenesis
/ drug effects
Pandemics
Pneumonia, Viral
/ drug therapy
Pyrazines
/ pharmacokinetics
RNA, Viral
/ genetics
RNA-Dependent RNA Polymerase
/ chemistry
SARS-CoV-2
Sequence Analysis
Vero Cells
Viral Nonstructural Proteins
/ chemistry
Virus Replication
/ drug effects
COVID-19 Drug Treatment
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
17 09 2020
17 09 2020
Historique:
received:
25
06
2020
accepted:
10
08
2020
entrez:
18
9
2020
pubmed:
19
9
2020
medline:
2
10
2020
Statut:
epublish
Résumé
The ongoing Corona Virus Disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has emphasized the urgent need for antiviral therapeutics. The viral RNA-dependent-RNA-polymerase (RdRp) is a promising target with polymerase inhibitors successfully used for the treatment of several viral diseases. We demonstrate here that Favipiravir predominantly exerts an antiviral effect through lethal mutagenesis. The SARS-CoV RdRp complex is at least 10-fold more active than any other viral RdRp known. It possesses both unusually high nucleotide incorporation rates and high-error rates allowing facile insertion of Favipiravir into viral RNA, provoking C-to-U and G-to-A transitions in the already low cytosine content SARS-CoV-2 genome. The coronavirus RdRp complex represents an Achilles heel for SARS-CoV, supporting nucleoside analogues as promising candidates for the treatment of COVID-19.
Identifiants
pubmed: 32943628
doi: 10.1038/s41467-020-18463-z
pii: 10.1038/s41467-020-18463-z
pmc: PMC7499305
doi:
Substances chimiques
Amides
0
Antiviral Agents
0
Pyrazines
0
RNA, Viral
0
T 1105
0
Viral Nonstructural Proteins
0
Coronavirus RNA-Dependent RNA Polymerase
EC 2.7.7.48
NSP12 protein, SARS-CoV-2
EC 2.7.7.48
RNA-Dependent RNA Polymerase
EC 2.7.7.48
favipiravir
EW5GL2X7E0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4682Subventions
Organisme : NIAID NIH HHS
ID : R01 AI059130
Pays : United States
Organisme : NIAID NIH HHS
ID : R37 AI059130
Pays : United States
Organisme : NIAID NIH HHS
ID : R56 AI059130
Pays : United States
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