Structural basis for inhibition of the SARS-CoV-2 RNA polymerase by suramin.
Animals
Antiviral Agents
/ chemistry
Binding Sites
Catalytic Domain
Chlorocebus aethiops
Coronavirus RNA-Dependent RNA Polymerase
/ antagonists & inhibitors
Cryoelectron Microscopy
Enzyme Inhibitors
/ chemistry
Protein Conformation
RNA, Viral
/ chemistry
SARS-CoV-2
/ drug effects
Suramin
/ chemistry
Vero Cells
Virus Replication
/ drug effects
Journal
Nature structural & molecular biology
ISSN: 1545-9985
Titre abrégé: Nat Struct Mol Biol
Pays: United States
ID NLM: 101186374
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
28
10
2020
accepted:
05
02
2021
pubmed:
7
3
2021
medline:
30
3
2021
entrez:
6
3
2021
Statut:
ppublish
Résumé
The COVID-19 pandemic caused by nonstop infections of SARS-CoV-2 has continued to ravage many countries worldwide. Here we report that suramin, a 100-year-old drug, is a potent inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and acts by blocking the binding of RNA to the enzyme. In biochemical assays, suramin and its derivatives are at least 20-fold more potent than remdesivir, the currently approved nucleotide drug for treatment of COVID-19. The 2.6 Å cryo-electron microscopy structure of the viral RdRp bound to suramin reveals two binding sites. One site directly blocks the binding of the RNA template strand and the other site clashes with the RNA primer strand near the RdRp catalytic site, thus inhibiting RdRp activity. Suramin blocks viral replication in Vero E6 cells, although the reasons underlying this effect are likely various. Our results provide a structural mechanism for a nonnucleotide inhibitor of the SARS-CoV-2 RdRp.
Identifiants
pubmed: 33674802
doi: 10.1038/s41594-021-00570-0
pii: 10.1038/s41594-021-00570-0
doi:
Substances chimiques
Antiviral Agents
0
Enzyme Inhibitors
0
RNA, Viral
0
Suramin
6032D45BEM
Coronavirus RNA-Dependent RNA Polymerase
EC 2.7.7.48
NSP12 protein, SARS-CoV-2
EC 2.7.7.48
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
319-325Subventions
Organisme : Science and Technology Commission of Shanghai Municipality (Shanghai Municipal Science and Technology Commission)
ID : 2019SHZDZX02
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