PubMed Journals: J Biol Chem
Source: PMID: 32094225⇦⇨ J Biol Chem. 2020 Feb 24. pii:
⇩ jbc.AC120.013056. doi:
10.1074/jbc.AC120.013056. [Epub ahead of
The antiviral compoundremdesivir potently
inhibits RNA-dependent RNA polymerase from
Middle East respiratory syndrome coronavirus.
Gordon CJ(1), Tchesnokov EP(1), Feng JY(2),
Porter DP(3), Gotte M(4).
(1) University of Alberta, Canada.
(2) Biology, Gilead Sciences, United States.
(3) Gilead, United States.
(4) Medical Microbiology and Immunology,
University of Alberta, Canada.
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 (SARS-CoV-2). Remdesivir (RDV) is an
investigational compound with a broad
spectrum of antiviral activities against RNA
viruses, including SARS-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 analogues. 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.
Published under license by The American
Society for Biochemistry and Molecular Biology,
DOI: 10.1074/jbc.AC120.013056PMID: 32094225⇧TweetPrint