The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus.
J Biol Chem
; 295(15): 4773-4779, 2020 04 10.
Article
in English
| MEDLINE | ID: covidwho-1988
ABSTRACT
Antiviral drugs for managing infections with human coronaviruses are not yet approved, posing a serious challenge to current global efforts aimed at containing the outbreak of severe acute respiratory syndrome-coronavirus 2 (CoV-2). Remdesivir (RDV) is an investigational compound with a broad spectrum of antiviral activities against RNA viruses, including severe acute respiratory syndrome-CoV and Middle East respiratory syndrome (MERS-CoV). RDV is a nucleotide analog inhibitor of RNA-dependent RNA polymerases (RdRps). Here, we co-expressed the MERS-CoV nonstructural proteins nsp5, nsp7, nsp8, and nsp12 (RdRp) in insect cells as a part a polyprotein to study the mechanism of inhibition of MERS-CoV RdRp by RDV. We initially demonstrated that nsp8 and nsp12 form an active complex. The triphosphate form of the inhibitor (RDV-TP) competes with its natural counterpart ATP. Of note, the selectivity value for RDV-TP obtained here with a steady-state approach suggests that it is more efficiently incorporated than ATP and two other nucleotide analogs. Once incorporated at position i, the inhibitor caused RNA synthesis arrest at position i + 3. Hence, the likely mechanism of action is delayed RNA chain termination. The additional three nucleotides may protect the inhibitor from excision by the viral 3'-5' exonuclease activity. Together, these results help to explain the high potency of RDV against RNA viruses in cell-based assays.
Keywords
Ebola virus (EBOV); Middle East respiratory syndrome coronavirus (MERSCoV); RNA chain termination; RNA-dependent RNA polymerase (RdRp); SARSCoV-2; antiviral drug; coronavirus; drug development; enzyme inhibitor; nucleoside/nucleotide analog; plus-stranded RNA virus; positive-sense RNA virus; remdesivir; viral polymerase; viral replicase
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Antiviral Agents
/
Virus Replication
/
RNA-Dependent RNA Polymerase
/
Adenosine Monophosphate
/
Nucleic Acid Synthesis Inhibitors
/
Alanine
/
Middle East Respiratory Syndrome Coronavirus
Limits:
Animals
Language:
English
Journal:
J Biol Chem
Year:
2020
Document Type:
Article
Affiliation country:
Jbc.AC120.013056
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