N-benzyl 4,4-disubstituted piperidines as a potent class of influenza H1N1 virus inhibitors showing a novel mechanism of hemagglutinin fusion peptide interaction.
Animals
Antiviral Agents
/ chemical synthesis
Dogs
Dose-Response Relationship, Drug
Hemagglutinin Glycoproteins, Influenza Virus
/ chemistry
Humans
Influenza A Virus, H1N1 Subtype
/ drug effects
Madin Darby Canine Kidney Cells
/ drug effects
Microbial Sensitivity Tests
Models, Molecular
Molecular Structure
Piperidines
/ chemical synthesis
Structure-Activity Relationship
Fusion peptide inhibitor
Hemagglutinin
Influenza virus
N-Benzyl-4,4,-disubstituted piperidines
Journal
European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510
Informations de publication
Date de publication:
15 May 2020
15 May 2020
Historique:
received:
04
02
2020
revised:
09
03
2020
accepted:
09
03
2020
pubmed:
30
3
2020
medline:
1
12
2020
entrez:
30
3
2020
Statut:
ppublish
Résumé
The influenza virus hemagglutinin (HA) is an attractive target for antiviral therapy due to its essential role in mediating virus entry into the host cell. We here report the identification of a class of N-benzyl-4,4,-disubstituted piperidines as influenza A virus fusion inhibitors with specific activity against the H1N1 subtype. Using the highly efficient one-step Ugi four-component reaction, diverse library of piperidine-based analogues was synthesized and evaluated to explore the structure-activity relationships (SAR). Mechanistic studies, including resistance selection with the most active compound (2) demonstrated that it acts as an inhibitor of the low pH-induced HA-mediated membrane fusion process. Computational studies identified an as yet unrecognized fusion inhibitor binding site, which is located at the bottom of the HA
Identifiants
pubmed: 32220685
pii: S0223-5234(20)30190-2
doi: 10.1016/j.ejmech.2020.112223
pii:
doi:
Substances chimiques
Antiviral Agents
0
Hemagglutinin Glycoproteins, Influenza Virus
0
Piperidines
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
112223Informations de copyright
Copyright © 2020 Elsevier Masson SAS. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.