Rimonabant suppresses RNA transcription of hepatitis B virus by inhibiting hepatocyte nuclear factor 4α.
Antiviral Agents
/ pharmacology
Drug Discovery
Hep G2 Cells
Hepatitis B virus
/ drug effects
Hepatocyte Nuclear Factor 4
/ antagonists & inhibitors
Hepatocytes
/ drug effects
Humans
RNA, Messenger
/ metabolism
RNA, Viral
/ metabolism
Receptors, G-Protein-Coupled
/ antagonists & inhibitors
Rimonabant
/ pharmacology
Virus Replication
/ drug effects
HBV
HNF4α
pgRNA
rimonabant
transcription
Journal
Microbiology and immunology
ISSN: 1348-0421
Titre abrégé: Microbiol Immunol
Pays: Australia
ID NLM: 7703966
Informations de publication
Date de publication:
May 2020
May 2020
Historique:
received:
10
01
2020
revised:
15
01
2020
accepted:
21
01
2020
pubmed:
26
1
2020
medline:
21
10
2020
entrez:
26
1
2020
Statut:
ppublish
Résumé
Chronic infection with hepatitis B virus (HBV) sometime induces lethal cirrhosis and hepatocellular carcinoma. Although nucleot(s)ide analogs are used as main treatment for HBV infection, the emergence of the drug-resistant viruses has become a problem. To discover novel antivirals with low side effects and low risk of emergence of resistant viruses, screening for anti-HBV compounds was performed with compound libraries of inhibitors targeting G-protein-coupled receptors (GPCRs). HepG2-hNTCP C4 cells infected with HBV were treated with various GPCR inhibitors and harvested at 14 day postinfection for quantification of core protein in the first screening or relaxed circular DNA in the second screening. Finally, we identified a cannabinoid receptor 1 inhibitor, rimonabant, as a candidate showing anti-HBV effect. In HepG2-hNTCP C4 cells, treatment with rimonabant suppressed HBV propagation at the viral RNA transcription step but had no effect on entry or covalently closed circular DNA level. The values of half maximal inhibitory concentration, half maximal effective concentration, and selectivity index of rimonabant in primary human hepatocyte (PHH) are 2.77 μm, 40.4 μm, and 14.6, respectively. Transcriptome analysis of rimonabant-treated primary hepatocytes by RNA sequencing revealed that the transcriptional activity of hepatocyte nuclear factor 4α (HNF4α), which is known to stimulate viral RNA synthesis, was depressed. By treatment of PHH with rimonabant, the expression level of HNF4α protein and the production of the messenger RNAs (mRNAs) of downstream factors promoted by HNF4α were reduced while the amount of HNF4α mRNA was not altered. These results suggest that treatment with rimonabant suppresses HBV propagation through the inhibition of HNF4α activity.
Identifiants
pubmed: 31981244
doi: 10.1111/1348-0421.12777
doi:
Substances chimiques
Antiviral Agents
0
HNF4A protein, human
0
Hepatocyte Nuclear Factor 4
0
RNA, Messenger
0
RNA, Viral
0
Receptors, G-Protein-Coupled
0
Rimonabant
RML78EN3XE
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
345-355Subventions
Organisme : Japan Agency for Medical Research and Development
ID : JP19fk0310102
Organisme : Japan Agency for Medical Research and Development
ID : JP19fk0310107
Organisme : Japan Agency for Medical Research and Development
ID : JP19fk0310111
Organisme : Japan Agency for Medical Research and Development
ID : JP19fk0310119
Informations de copyright
© 2020 The Societies and John Wiley & Sons Australia, Ltd.
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