Identification, design and synthesis of novel pyrazolopyridine influenza virus nonstructural protein 1 antagonists.
Animals
Antiviral Agents
/ chemical synthesis
Dogs
Drug Design
HEK293 Cells
Half-Life
Humans
Influenza A virus
/ metabolism
Interferon-beta
/ metabolism
Madin Darby Canine Kidney Cells
Male
Mice
Mice, Inbred C57BL
Pyrazoles
/ chemistry
Pyridines
/ chemistry
Structure-Activity Relationship
Viral Nonstructural Proteins
/ antagonists & inhibitors
Virus Replication
/ drug effects
Antagonist
Antiviral
Influenza
NS1
Pyrazolopyridine
Journal
Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377
Informations de publication
Date de publication:
01 05 2019
01 05 2019
Historique:
received:
01
02
2019
revised:
21
02
2019
accepted:
26
02
2019
pubmed:
11
3
2019
medline:
20
2
2020
entrez:
11
3
2019
Statut:
ppublish
Résumé
Nonstructural protein 1 (NS1) plays a crucial function in the replication, spread, and pathogenesis of influenza virus by inhibiting the host innate immune response. Here we report the discovery and optimization of novel pyrazolopyridine NS1 antagonists that can potently inhibit influenza A/PR/8/34 replication in MDCK cells, rescue MDCK cells from cytopathic effects of seasonal influenza A strains, reverse NS1-dependent inhibition of IFN-β gene expression, and suppress the slow growth phenotype in NS1-expressing yeast. These pyrazolopyridines will enable researchers to investigate NS1 function during infection and how antagonists can be utilized in the next generation of treatments for influenza infection.
Identifiants
pubmed: 30852083
pii: S0960-894X(19)30111-8
doi: 10.1016/j.bmcl.2019.02.027
pmc: PMC8290212
mid: NIHMS1523408
pii:
doi:
Substances chimiques
Antiviral Agents
0
INS1 protein, influenza virus
0
Pyrazoles
0
Pyridines
0
Viral Nonstructural Proteins
0
pyrazolopyridine
0
Interferon-beta
77238-31-4
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1113-1119Subventions
Organisme : Intramural NIH HHS
ID : Z99 TR999999
Pays : United States
Organisme : NIAID NIH HHS
ID : HHSN272201100019C
Pays : United States
Organisme : NIAID NIH HHS
ID : HHSN272201100019I
Pays : United States
Organisme : NIMH NIH HHS
ID : R03 MH085680
Pays : United States
Organisme : NIAID NIH HHS
ID : R44 AI084244
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.
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