Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A.
Adenosine Monophosphate
/ analogs & derivatives
Alanine
/ analogs & derivatives
Animals
Antiviral Agents
/ pharmacology
COVID-19
/ prevention & control
Coronavirus Nucleocapsid Proteins
/ biosynthesis
Depsipeptides
/ administration & dosage
Drug Evaluation, Preclinical
Female
HEK293 Cells
Humans
Lung
/ virology
Mice, Inbred C57BL
Mutation
Peptide Elongation Factor 1
/ antagonists & inhibitors
Peptides, Cyclic
Phosphoproteins
/ biosynthesis
RNA, Viral
/ biosynthesis
SARS-CoV-2
/ drug effects
Virus Replication
/ drug effects
COVID-19 Drug Treatment
Journal
Science (New York, N.Y.)
ISSN: 1095-9203
Titre abrégé: Science
Pays: United States
ID NLM: 0404511
Informations de publication
Date de publication:
26 02 2021
26 02 2021
Historique:
received:
28
10
2020
accepted:
20
01
2021
pubmed:
27
1
2021
medline:
6
3
2021
entrez:
26
1
2021
Statut:
ppublish
Résumé
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins interact with the eukaryotic translation machinery, and inhibitors of translation have potent antiviral effects. We found that the drug plitidepsin (aplidin), which has limited clinical approval, possesses antiviral activity (90% inhibitory concentration = 0.88 nM) that is more potent than remdesivir against SARS-CoV-2 in vitro by a factor of 27.5, with limited toxicity in cell culture. Through the use of a drug-resistant mutant, we show that the antiviral activity of plitidepsin against SARS-CoV-2 is mediated through inhibition of the known target eEF1A (eukaryotic translation elongation factor 1A). We demonstrate the in vivo efficacy of plitidepsin treatment in two mouse models of SARS-CoV-2 infection with a reduction of viral replication in the lungs by two orders of magnitude using prophylactic treatment. Our results indicate that plitidepsin is a promising therapeutic candidate for COVID-19.
Identifiants
pubmed: 33495306
pii: science.abf4058
doi: 10.1126/science.abf4058
pmc: PMC7963220
doi:
Substances chimiques
Antiviral Agents
0
Coronavirus Nucleocapsid Proteins
0
Depsipeptides
0
EEF1A1 protein, human
0
Peptide Elongation Factor 1
0
Peptides, Cyclic
0
Phosphoproteins
0
RNA, Viral
0
nucleocapsid phosphoprotein, SARS-CoV-2
0
remdesivir
3QKI37EEHE
Adenosine Monophosphate
415SHH325A
Alanine
OF5P57N2ZX
plitidepsin
Y76ID234HW
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
926-931Subventions
Organisme : NIAID NIH HHS
ID : HHSN272201400008C
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI120694
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI135990
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI122747
Pays : United States
Organisme : NCI NIH HHS
ID : F32 CA239333
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA221969
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA244550
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI135972
Pays : United States
Organisme : NIAID NIH HHS
ID : P01 AI063302
Pays : United States
Organisme : NIAID NIH HHS
ID : P50 AI150476
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI143292
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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