BAY 41-4109-mediated aggregation of assembled and misassembled HBV capsids in cells revealed by electron microscopy.
Antiviral Agents
/ pharmacology
Capsid
/ drug effects
Capsid Proteins
/ metabolism
Cell Line
Hepatitis B Core Antigens
/ metabolism
Hepatitis B virus
/ drug effects
Humans
Microscopy, Electron
/ methods
Protein Aggregates
/ drug effects
Pyridines
/ pharmacology
Pyrimidines
/ pharmacology
Virus Assembly
/ drug effects
Aggregation
CAMs
Confocal microscopy
Electron microscopy
HBV
HBc
Journal
Antiviral research
ISSN: 1872-9096
Titre abrégé: Antiviral Res
Pays: Netherlands
ID NLM: 8109699
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
09
05
2019
revised:
05
07
2019
accepted:
10
07
2019
pubmed:
16
7
2019
medline:
8
7
2020
entrez:
15
7
2019
Statut:
ppublish
Résumé
HBc is a small protein essential for the formation of the icosahedral HBV capsid. Its multiple roles in the replication cycle make this protein a promising target for the development of antiviral molecules. Based on the structure of HBc, a series of HBV assembly inhibitors, also known as capsid assembly modulators, were identified. We investigated the effect of BAY 41-4109, a heteroaryldihydropyrimidine derivative that promotes the assembly of a non-capsid polymer. We showed, by confocal microscopy, that BAY 41-4109 mediated HBc aggregation, mostly in the cytoplasm of Huh7 cells. Image analysis revealed that aggregate size depended on BAY 41-4109 concentration and treatment duration. Large aggregates in the vicinity of the nucleus were enclosed by invaginations of the nuclear envelope. This deformation of the nuclear envelope was confirmed by transmission electron microscopy (TEM) and immuno-TEM. These two techniques also revealed that the HBc aggregates were accumulations of capsid-like shells with an electron-dense material consisting of HBV core fragments. These findings, shedding light on the ultrastructural organization of HBc aggregates, provide insight into the mechanisms of action of BAY 41-4109 against HBV and will serve as a basis for comparison with other HBV capsid assembly inhibitors.
Identifiants
pubmed: 31302151
pii: S0166-3542(19)30265-7
doi: 10.1016/j.antiviral.2019.104557
pii:
doi:
Substances chimiques
Antiviral Agents
0
BAY 41-4109
0
Capsid Proteins
0
Hepatitis B Core Antigens
0
Protein Aggregates
0
Pyridines
0
Pyrimidines
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
104557Informations de copyright
Copyright © 2019. Published by Elsevier B.V.