Structure of the SARS-CoV-2 RNA-dependent RNA polymerase in the presence of favipiravir-RTP.
COVID-19
T-705
cryoEM
drug design
structural biology
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
16 02 2021
16 02 2021
Historique:
entrez:
2
2
2021
pubmed:
3
2
2021
medline:
17
2
2021
Statut:
ppublish
Résumé
The RNA polymerase inhibitor favipiravir is currently in clinical trials as a treatment for infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), despite limited information about the molecular basis for its activity. Here we report the structure of favipiravir ribonucleoside triphosphate (favipiravir-RTP) in complex with the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) bound to a template:primer RNA duplex, determined by electron cryomicroscopy (cryoEM) to a resolution of 2.5 Å. The structure shows clear evidence for the inhibitor at the catalytic site of the enzyme, and resolves the conformation of key side chains and ions surrounding the binding pocket. Polymerase activity assays indicate that the inhibitor is weakly incorporated into the RNA primer strand, and suppresses RNA replication in the presence of natural nucleotides. The structure reveals an unusual, nonproductive binding mode of favipiravir-RTP at the catalytic site of SARS-CoV-2 RdRp, which explains its low rate of incorporation into the RNA primer strand. Together, these findings inform current and future efforts to develop polymerase inhibitors for SARS coronaviruses.
Identifiants
pubmed: 33526596
pii: 2021946118
doi: 10.1073/pnas.2021946118
pmc: PMC7896311
pii:
doi:
Substances chimiques
Amides
0
Enzyme Inhibitors
0
Pyrazines
0
Ribonucleotides
0
Coronavirus RNA-Dependent RNA Polymerase
EC 2.7.7.48
favipiravir
EW5GL2X7E0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Medical Research Council
ID : MC_U105184326
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UP_1201/6
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UP_1201/17
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 2027541Z/16/Z
Pays : United Kingdom
Informations de copyright
Copyright © 2021 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
The authors declare no competing interest.
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