Back to Search
Start Over
Rapid incorporation of Favipiravir by the fast and permissive viral RNA polymerase complex results in SARS-CoV-2 lethal mutagenesis
- Source :
- Nature Communications, Nature Communications, 2020, 11 (1), pp.4682. ⟨10.1038/s41467-020-18463-z⟩, Nature Communications, Vol 11, Iss 1, Pp 1-9 (2020), Nature Communications, Nature Publishing Group, 2020, 11 (1), pp.4682. ⟨10.1038/s41467-020-18463-z⟩
- Publication Year :
- 2020
- Publisher :
- HAL CCSD, 2020.
-
Abstract
- 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.<br />Favipiravir (T-705) is an inhibitor of viral RNA-dependent-RNA-polymerases (RdRp) and clinical trials for the treatment of COVID-19 are ongoing. Here, the authors show that SARS-CoV nsp12 is the fastest known viral RdRp and they provide insights into the mechanism of action of Favipiravir, demonstrating that its antiviral effect on SARS-CoV-2 is primarily mediated through lethal mutagenesis.
- Subjects :
- Models, Molecular
Science
viruses
Pneumonia, Viral
Viral Nonstructural Proteins
[SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology
Virus Replication
Antiviral Agents
Article
Betacoronavirus
Chlorocebus aethiops
Animals
lcsh:Science
Pandemics
Vero Cells
[SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology
Coronavirus RNA-Dependent RNA Polymerase
SARS-CoV-2
COVID-19
[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology
Viral proteins
RNA-Dependent RNA Polymerase
Amides
COVID-19 Drug Treatment
Mutagenesis
[SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology
Pyrazines
[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology
[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology
RNA, Viral
lcsh:Q
Coronavirus Infections
Sequence Analysis
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Database :
- OpenAIRE
- Journal :
- Nature Communications, Nature Communications, 2020, 11 (1), pp.4682. ⟨10.1038/s41467-020-18463-z⟩, Nature Communications, Vol 11, Iss 1, Pp 1-9 (2020), Nature Communications, Nature Publishing Group, 2020, 11 (1), pp.4682. ⟨10.1038/s41467-020-18463-z⟩
- Accession number :
- edsair.pmid.dedup....305a4e7cfba45bea18eb9ae104c5a294