Oral prodrug of remdesivir parent GS-441524 is efficacious against SARS-CoV-2 in ferrets.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
05 11 2021
05 11 2021
Historique:
received:
30
07
2021
accepted:
22
10
2021
entrez:
6
11
2021
pubmed:
7
11
2021
medline:
24
12
2021
Statut:
epublish
Résumé
Remdesivir is an antiviral approved for COVID-19 treatment, but its wider use is limited by intravenous delivery. An orally bioavailable remdesivir analog may boost therapeutic benefit by facilitating early administration to non-hospitalized patients. This study characterizes the anti-SARS-CoV-2 efficacy of GS-621763, an oral prodrug of remdesivir parent nucleoside GS-441524. Both GS-621763 and GS-441524 inhibit SARS-CoV-2, including variants of concern (VOC) in cell culture and human airway epithelium organoids. Oral GS-621763 is efficiently converted to plasma metabolite GS-441524, and in lungs to the triphosphate metabolite identical to that generated by remdesivir, demonstrating a consistent mechanism of activity. Twice-daily oral administration of 10 mg/kg GS-621763 reduces SARS-CoV-2 burden to near-undetectable levels in ferrets. When dosed therapeutically against VOC P.1 gamma γ, oral GS-621763 blocks virus replication and prevents transmission to untreated contact animals. These results demonstrate therapeutic efficacy of a much-needed orally bioavailable analog of remdesivir in a relevant animal model of SARS-CoV-2 infection.
Identifiants
pubmed: 34741049
doi: 10.1038/s41467-021-26760-4
pii: 10.1038/s41467-021-26760-4
pmc: PMC8571282
doi:
Substances chimiques
Antiviral Agents
0
Prodrugs
0
GS-441524
1BQK176DT6
Adenosine
K72T3FS567
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
6415Subventions
Organisme : NIAID NIH HHS
ID : R01 AI141222
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI161175
Pays : United States
Organisme : Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)
ID : AI141222
Organisme : Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)
ID : AI153400
Informations de copyright
© 2021. The Author(s).
Références
Antimicrob Agents Chemother. 2021 Mar 18;65(4):
pubmed: 33558299
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Science. 2021 Jan 8;371(6525):172-177
pubmed: 33172935
J Med Chem. 2021 Apr 22;64(8):5001-5017
pubmed: 33835812
J Med Chem. 2017 Mar 9;60(5):1648-1661
pubmed: 28124907
Nucleic Acids Res. 2010 Sep;38(16):e164
pubmed: 20601685
N Engl J Med. 2021 May 13;384(19):1866-1868
pubmed: 33761203
Clin Transl Sci. 2020 Sep;13(5):896-906
pubmed: 32589775
J Clin Microbiol. 2016 Dec 28;55(1):177-182
pubmed: 27795347
J Infect Dis. 2021 Apr 8;223(7):1132-1138
pubmed: 33388780
Methods Mol Biol. 2012;838:369-84
pubmed: 22228022
Bioorg Med Chem. 2021 Sep 15;46:116364
pubmed: 34450570
Clin Pharmacokinet. 2021 May;60(5):569-583
pubmed: 33782830
N Engl J Med. 2020 Feb 20;382(8):727-733
pubmed: 31978945
Bioinformatics. 2014 Aug 1;30(15):2114-20
pubmed: 24695404
J Virol. 2005 Mar;79(6):3846-50
pubmed: 15731278
mBio. 2020 May 22;11(3):
pubmed: 32444382
Nat Commun. 2020 Jul 8;11(1):3496
pubmed: 32641684
J Biol Chem. 2020 Nov 20;295(47):16156-16165
pubmed: 32967965
Science. 2021 Apr 9;372(6538):
pubmed: 33658326
mBio. 2018 Mar 6;9(2):
pubmed: 29511076
Proc Natl Acad Sci U S A. 2020 Mar 24;117(12):6771-6776
pubmed: 32054787
J Med Chem. 2021 Feb 1;:
pubmed: 33523654
Science. 2021 May 21;372(6544):815-821
pubmed: 33853970
Clin Immunol. 2020 Nov;220:108588
pubmed: 32905851
Nat Microbiol. 2021 Jan;6(1):11-18
pubmed: 33273742
Sci Transl Med. 2019 Oct 23;11(515):
pubmed: 31645453
Proc Natl Acad Sci U S A. 2020 Oct 27;117(43):26946-26954
pubmed: 33028676
J Clin Microbiol. 2020 Dec 17;59(1):
pubmed: 33046529
Science. 2020 May 29;368(6494):1016-1020
pubmed: 32269068
Antimicrob Agents Chemother. 2021 Mar 1;:
pubmed: 33649113
Bioinformatics. 2009 Sep 1;25(17):2283-5
pubmed: 19542151
PLoS Pathog. 2021 Jan 28;17(1):e1009292
pubmed: 33507952
Cell Rep. 2020 Jul 21;32(3):107940
pubmed: 32668216
N Engl J Med. 2020 Nov 5;383(19):1813-1826
pubmed: 32445440
Nat Med. 2021 Mar;27(3):401-410
pubmed: 33723456
J Biol Chem. 2020 May 15;295(20):6785-6797
pubmed: 32284326
Nature. 2020 Sep;585(7824):273-276
pubmed: 32516797
Nat Commun. 2021 Mar 12;12(1):1653
pubmed: 33712573