Article ; Online: Rapid incorporation of Favipiravir by the fast and permissive viral RNA polymerase complex results in SARS-CoV-2 lethal mutagenesis.
2020 Volume 11, Issue 1, Page(s) 4682
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 ... ...
| 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. |
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| MeSH term(s) | Amides/pharmacokinetics ; Amides/pharmacology ; Animals ; Antiviral Agents/pharmacokinetics ; Antiviral Agents/pharmacology ; Betacoronavirus/drug effects ; Betacoronavirus/genetics ; COVID-19 ; Chlorocebus aethiops ; Coronavirus Infections/drug therapy ; Coronavirus Infections/virology ; Coronavirus RNA-Dependent RNA Polymerase ; Models, Molecular ; Mutagenesis/drug effects ; Pandemics ; Pneumonia, Viral/drug therapy ; Pneumonia, Viral/virology ; Pyrazines/pharmacokinetics ; Pyrazines/pharmacology ; RNA, Viral/genetics ; RNA, Viral/metabolism ; RNA-Dependent RNA Polymerase/chemistry ; RNA-Dependent RNA Polymerase/metabolism ; SARS-CoV-2 ; Sequence Analysis ; Vero Cells ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/metabolism ; Virus Replication/drug effects ; COVID-19 Drug Treatment |
| Chemical Substances | Amides ; Antiviral Agents ; Pyrazines ; RNA, Viral ; T 1105 ; Viral Nonstructural Proteins ; 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) |
| Keywords | covid19 |
| Language | English |
| Publishing date | 2020-09-17 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2553671-0 |
| ISSN | 2041-1723 ; 2041-1723 |
| ISSN (online) | 2041-1723 |
| ISSN | 2041-1723 |
| DOI | 10.1038/s41467-020-18463-z |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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