Remdesivir targets a structurally analogous region of the Ebola virus and SARS-CoV-2 polymerases.
Adenosine Monophosphate
/ analogs & derivatives
Alanine
/ analogs & derivatives
Antiviral Agents
/ pharmacology
Betacoronavirus
/ chemistry
Cell Line
Drug Tolerance
/ genetics
Ebolavirus
/ drug effects
Humans
Models, Molecular
Mutation
RNA-Dependent RNA Polymerase
/ chemistry
SARS-CoV-2
Viral Nonstructural Proteins
/ chemistry
Virus Replication
/ drug effects
COVID-19
Ebola
SARS-CoV-2
antiviral nucleotide analog
remdesivir
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:
27 10 2020
27 10 2020
Historique:
pubmed:
9
10
2020
medline:
11
11
2020
entrez:
8
10
2020
Statut:
ppublish
Résumé
Remdesivir is a broad-spectrum antiviral nucleotide prodrug that has been clinically evaluated in Ebola virus patients and recently received emergency use authorization (EUA) for treatment of COVID-19. With approvals from the Federal Select Agent Program and the Centers for Disease Control and Prevention's Institutional Biosecurity Board, we characterized the resistance profile of remdesivir by serially passaging Ebola virus under remdesivir selection; we generated lineages with low-level reduced susceptibility to remdesivir after 35 passages. We found that a single amino acid substitution, F548S, in the Ebola virus polymerase conferred low-level reduced susceptibility to remdesivir. The F548 residue is highly conserved in filoviruses but should be subject to specific surveillance among novel filoviruses, in newly emerging variants in ongoing outbreaks, and also in Ebola virus patients undergoing remdesivir therapy. Homology modeling suggests that the Ebola virus polymerase F548 residue lies in the F-motif of the polymerase active site, a region that was previously identified as susceptible to resistance mutations in coronaviruses. Our data suggest that molecular surveillance of this region of the polymerase in remdesivir-treated COVID-19 patients is also warranted.
Identifiants
pubmed: 33028676
pii: 2012294117
doi: 10.1073/pnas.2012294117
pmc: PMC7604432
doi:
Substances chimiques
Antiviral Agents
0
Viral Nonstructural Proteins
0
remdesivir
3QKI37EEHE
Adenosine Monophosphate
415SHH325A
RNA-Dependent RNA Polymerase
EC 2.7.7.48
Alanine
OF5P57N2ZX
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
26946-26954Informations de copyright
Copyright © 2020 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
Competing interest statement: The authors affiliated with Gilead Sciences are employees of the company and may own company stock; R.J. holds a patent on the use of remdesivir to treat filovirus infections. The authors affiliated with the Centers for Disease Control and Prevention have no conflict of interest to report.
Références
Front Microbiol. 2019 Aug 22;10:1945
pubmed: 31507560
Nature. 2008 Feb 21;451(7181):990-3
pubmed: 18288193
Virology. 2015 Oct;484:259-264
pubmed: 26122472
Sci Rep. 2018 Mar 5;8(1):3970
pubmed: 29507309
J Med Chem. 2017 Mar 9;60(5):1648-1661
pubmed: 28124907
Nat Commun. 2019 May 28;10(1):2342
pubmed: 31138817
PLoS Pathog. 2018 Feb 9;14(2):e1006889
pubmed: 29425244
Sci Transl Med. 2019 May 29;11(494):
pubmed: 31142680
Nature. 2020 Jan;577(7789):275-279
pubmed: 31698413
PLoS One. 2019 Mar 21;14(3):e0211093
pubmed: 30897171
J Virol. 2015 Dec 16;90(5):2345-55
pubmed: 26676781
PLoS Pathog. 2008 Nov;4(11):e1000212
pubmed: 19023410
Sci Transl Med. 2017 Jun 28;9(396):
pubmed: 28659436
Bioinformatics. 2014 Aug 1;30(15):2114-20
pubmed: 24695404
Nature. 2020 Aug;584(7819):154-156
pubmed: 32438371
Sci Rep. 2017 Mar 06;7:43395
pubmed: 28262699
PeerJ. 2016 Feb 16;4:e1674
pubmed: 26925318
J Biol Chem. 2020 Nov 20;295(47):16156-16165
pubmed: 32967965
Viruses. 2019 Apr 04;11(4):
pubmed: 30987343
Cell. 2019 Sep 19;179(1):193-204.e14
pubmed: 31495574
mBio. 2018 Mar 6;9(2):
pubmed: 29511076
Proc Natl Acad Sci U S A. 2020 Mar 24;117(12):6771-6776
pubmed: 32054787
N Engl J Med. 2019 Dec 12;381(24):2293-2303
pubmed: 31774950
J Biol Chem. 2020 Apr 10;295(15):4773-4779
pubmed: 32094225
Nature. 2016 Mar 17;531(7594):381-5
pubmed: 26934220
Bioinformatics. 2014 Mar 1;30(5):614-20
pubmed: 24142950
Cell Rep. 2020 Jul 21;32(3):107940
pubmed: 32668216
N Engl J Med. 2020 Nov 5;383(19):1813-1826
pubmed: 32445440
Mol Biol Evol. 2016 Jul;33(7):1870-4
pubmed: 27004904
J Biol Chem. 2020 May 15;295(20):6785-6797
pubmed: 32284326
J Antimicrob Chemother. 2014 Aug;69(8):2123-31
pubmed: 24710028
Antiviral Res. 2016 Dec;136:9-18
pubmed: 27771389
Nucleic Acids Res. 2014 Jul;42(Web Server issue):W320-4
pubmed: 24753421
Nature. 2014 Apr 17;508(7496):402-5
pubmed: 24590073