A Small Molecule, 4-Phenylbutyric Acid, Suppresses HCV Replication via Epigenetically Induced Hepatic Hepcidin.

Abstract

Hepatic hepcidin is a well-known major iron regulator and has been reported to be closely related to hepatitis C virus (HCV) replication. However, pharmacological targeting of the hepcidin in HCV replication has not been reported. A short-chain fatty acid, 4-Phenyl butyrate (4-PBA), is an acid chemical chaperone that acts as a histone deacetylase inhibitor (HDACi) to promote chromosomal histone acetylation. Here, we investigated the therapeutic effect of 4-PBA on hepcidin expression and HCV replication. We used HCV genotype 1b Huh 7.5-Con1 replicon cells and engraftment of NOD/SCID mice as in vitro and in vivo models to test the effect of 4-PBA. It was found that 4-PBA inhibited HCV replication in Huh7.5-Con1 replicon cells in a concentration- and time-dependent manner through the induction of hepcidin expression by epigenetic modification and subsequent upregulation of interferon-α signaling. HCV formed a membranous web composed of double-membrane vesicles and was utilized for RNA replication. Moreover, 4-PBA also disrupted the integrity of the membranous web and interfered with the molecular interactions critical for the assembly of the HCV replication complex. These findings suggest that 4-PBA is a key epigenetic inducer of anti-HCV hepatic hepcidin and might at least in part play a role in targeting host factors related to HCV infection as an attractive complement to current HCV therapies.

• Authors: Kiyoon Kim, Young-Seok Lee, Suyun Jeong, Daehong Kim, Suk Chon, Youngmi Kim Pak, Sungsoo Kim, Joohun Ha, Insug Kang, Wonchae Choe
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 15 (Aug 01 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 32752233 (Publication Type: Journal Article)

Chemical References

• Hepcidins
• Phenylbutyrates
• Small Molecule Libraries
• 4-phenylbutyric acid

Topics

• Animals
• Cell Line, Tumor
• Epigenesis, Genetic (drug effects)
• Gene Expression (drug effects)
• Hepacivirus (drug effects, genetics, physiology)
• Hepatitis C (prevention & control, virology)
• Hepcidins (genetics, metabolism)
• Host-Pathogen Interactions (drug effects)
• Humans
• Liver (drug effects, metabolism)
• Mice, Inbred NOD
• Mice, SCID
• Molecular Structure
• Phenylbutyrates (chemistry, pharmacology)
• Small Molecule Libraries (chemistry, pharmacology)
• Virus Replication (drug effects, genetics)