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Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency

The Journal of biological chemistry, 2020-05, Vol.295 (20), p.6785-6797 [Peer Reviewed Journal]

2020 © 2020 Gordon et al. ;2020 Gordon et al. ;2020 Gordon et al. 2020 Gordon et al. ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1074/jbc.RA120.013679 ;PMID: 32284326

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Title:
Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency
Author: Gordon, Calvin J. ; Tchesnokov, Egor P. ; Woolner, Emma ; Perry, Jason K. ; Feng, Joy Y. ; Porter, Danielle P. ; Götte, Matthias
Subjects: Adenosine Monophosphate - analogs & derivatives ; Adenosine Monophosphate - pharmacology ; Alanine - analogs & derivatives ; Alanine - pharmacology ; Animals ; Antiviral Agents - pharmacology ; Betacoronavirus - enzymology ; Betacoronavirus - physiology ; coronavirus (CoV) ; COVID-19 ; drug action ; drug development ; drug discovery ; Ebola virus ; Editors' Picks ; favipiravir ; Lassa virus ; MERS ; Models, Molecular ; plus-stranded RNA virus ; remdesivir ; replication ; ribavirin ; RNA polymerase ; RNA-dependent RNA polymerase (RdRp) ; RNA-Dependent RNA Polymerase - antagonists & inhibitors ; SARS ; SARS-CoV-2 ; Sf9 Cells ; sofosbuvir ; Spodoptera ; Virus Replication - drug effects
Is Part Of: The Journal of biological chemistry, 2020-05, Vol.295 (20), p.6785-6797
Description: Effective treatments for coronavirus disease 2019 (COVID-19) are urgently needed to control this current pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Replication of SARS-CoV-2 depends on the viral RNA-dependent RNA polymerase (RdRp), which is the likely target of the investigational nucleotide analogue remdesivir (RDV). RDV shows broad-spectrum antiviral activity against RNA viruses, and previous studies with RdRps from Ebola virus and Middle East respiratory syndrome coronavirus (MERS-CoV) have revealed that delayed chain termination is RDV's plausible mechanism of action. Here, we expressed and purified active SARS-CoV-2 RdRp composed of the nonstructural proteins nsp8 and nsp12. Enzyme kinetics indicated that this RdRp efficiently incorporates the active triphosphate form of RDV (RDV-TP) into RNA. Incorporation of RDV-TP at position i caused termination of RNA synthesis at position i+3. We obtained almost identical results with SARS-CoV, MERS-CoV, and SARS-CoV-2 RdRps. A unique property of RDV-TP is its high selectivity over incorporation of its natural nucleotide counterpart ATP. In this regard, the triphosphate forms of 2′-C-methylated compounds, including sofosbuvir, approved for the management of hepatitis C virus infection, and the broad-acting antivirals favipiravir and ribavirin, exhibited significant deficits. Furthermore, we provide evidence for the target specificity of RDV, as RDV-TP was less efficiently incorporated by the distantly related Lassa virus RdRp, and termination of RNA synthesis was not observed. These results collectively provide a unifying, refined mechanism of RDV-mediated RNA synthesis inhibition in coronaviruses and define this nucleotide analogue as a direct-acting antiviral.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 0021-9258
EISSN: 1083-351X
DOI: 10.1074/jbc.RA120.013679
PMID: 32284326
Source: MEDLINE
PubMed Central
Alma/SFX Local Collection

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Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency

2020 © 2020 Gordon et al. ;2020 Gordon et al. ;2020 Gordon et al. 2020 Gordon et al. ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1074/jbc.RA120.013679 ;PMID: 32284326

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