The oral protease inhibitor (PF-07321332) protects Syrian hamsters against infection with SARS-CoV-2 variants of concern.
A549 Cells
Administration, Oral
Animals
COVID-19
/ prevention & control
Chlorocebus aethiops
Coronavirus 3C Proteases
/ antagonists & inhibitors
Cricetinae
Disease Models, Animal
Humans
Lactams
/ administration & dosage
Leucine
/ administration & dosage
Mesocricetus
Nitriles
/ administration & dosage
Proline
/ administration & dosage
Respiratory Mucosa
/ drug effects
SARS-CoV-2
/ drug effects
Vero Cells
Viral Protease Inhibitors
/ administration & dosage
Virus Replication
/ drug effects
COVID-19 Drug Treatment
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
15 02 2022
15 02 2022
Historique:
received:
04
11
2021
accepted:
18
01
2022
entrez:
16
2
2022
pubmed:
17
2
2022
medline:
25
2
2022
Statut:
epublish
Résumé
There is an urgent need for potent and selective antivirals against SARS-CoV-2. Pfizer developed PF-07321332 (PF-332), a potent inhibitor of the viral main protease (Mpro, 3CLpro) that can be dosed orally and that is in clinical development. We here report that PF-332 exerts equipotent in vitro activity against the four SARS-CoV-2 variants of concerns (VoC) and that it can completely arrest replication of the alpha variant in primary human airway epithelial cells grown at the air-liquid interface. Treatment of Syrian Golden hamsters with PF-332 (250 mg/kg, twice daily) completely protected the animals against intranasal infection with the beta (B.1.351) and delta (B.1.617.2) SARS-CoV-2 variants. Moreover, treatment of SARS-CoV-2 (B.1.617.2) infected animals with PF-332 completely prevented transmission to untreated co-housed sentinels.
Identifiants
pubmed: 35169114
doi: 10.1038/s41467-022-28354-0
pii: 10.1038/s41467-022-28354-0
pmc: PMC8847371
doi:
Substances chimiques
Lactams
0
Nitriles
0
Viral Protease Inhibitors
0
nirmatrelvir
7R9A5P7H32
Proline
9DLQ4CIU6V
3C-like proteinase, SARS-CoV-2
EC 3.4.22.-
Coronavirus 3C Proteases
EC 3.4.22.28
Leucine
GMW67QNF9C
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
719Subventions
Organisme : EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)
ID : No 101003627 (SCORE project)
Organisme : Wellcome Trust (Wellcome)
ID : the Wellcome TrustGrant ref: 222489/Z/21/Z
Organisme : Bill and Melinda Gates Foundation (Bill & Melinda Gates Foundation)
ID : INV-00636
Organisme : Fonds Wetenschappelijk Onderzoek (Research Foundation Flanders)
ID : FWO (G0G4820N)
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s).
Références
Nat Struct Mol Biol. 2021 Sep;28(9):740-746
pubmed: 34381216
J Virol Methods. 2005 Oct;129(1):56-63
pubmed: 15961169
Nat Commun. 2021 Oct 18;12(1):6055
pubmed: 34663813
EBioMedicine. 2021 Oct;72:103595
pubmed: 34571361
Biochem Biophys Res Commun. 2005 Apr 15;329(3):934-40
pubmed: 15752746
Antiviral Res. 2021 Aug;192:105122
pubmed: 34186107
J Med Virol. 2020 Apr;92(4):418-423
pubmed: 31967327
J Virol Methods. 2012 Aug;183(2):176-9
pubmed: 22575574
EBioMedicine. 2021 Jun;68:103403
pubmed: 34049240
Nature. 2020 Jun;582(7811):289-293
pubmed: 32272481
Proc Natl Acad Sci U S A. 2020 Oct 27;117(43):26955-26965
pubmed: 33037151
J Med Chem. 2016 Jul 28;59(14):6595-628
pubmed: 26878082
Comput Methods Programs Biomed. 2004 Aug;75(2):85-94
pubmed: 15212851
Cell Host Microbe. 2021 Apr 14;29(4):508-515
pubmed: 33789086
Comput Methods Programs Biomed. 2011 Jan;101(1):72-9
pubmed: 20627442
Nat Commun. 2021 Jan 12;12(1):279
pubmed: 33436624
Science. 2021 Dec 24;374(6575):1586-1593
pubmed: 34726479
Bioorg Med Chem Lett. 2020 Sep 1;30(17):127377
pubmed: 32738988
Nat Commun. 2020 Nov 17;11(1):5838
pubmed: 33203860
J Infect Dis. 2021 Sep 1;224(5):749-753
pubmed: 34244768