A Novel Tricyclic Polyketide, Vanitaracin A, Specifically Inhibits the Entry of Hepatitis B and D Viruses by Targeting Sodium Taurocholate Cotransporting Polypeptide.

Abstract

UNLABELLED:

Anti-hepatitis B virus (HBV) drugs are currently limited to nucleos(t)ide analogs (NAs) and interferons. A challenge of drug development is the identification of small molecules that suppress HBV infection from new chemical sources. Here, from a fungus-derived secondary metabolite library, we identify a structurally novel tricyclic polyketide, named vanitaracin A, which specifically inhibits HBV infection. Vanitaracin A inhibited the viral entry process with a submicromolar 50% inhibitory concentration (IC50) (IC50 = 0.61 ± 0.23 μM), without evident cytotoxicity (50% cytotoxic concentration of >256 μM; selectivity index value of >419) in primary human hepatocytes. Vanitaracin A did not affect the HBV replication process. This compound was found to directly interact with the HBV entry receptor sodium taurocholate cotransporting polypeptide (NTCP) and impaired its bile acid transport activity. Consistent with this NTCP targeting, antiviral activity of vanitaracin A was observed with hepatitis D virus (HDV) but not hepatitis C virus. Importantly, vanitaracin A inhibited infection by all HBV genotypes tested (genotypes A to D) and clinically relevant NA-resistant HBV isolate. Thus, we identified a fungal metabolite, vanitaracin A, which was a potent, well-tolerated, and broadly active inhibitor of HBV and HDV entry. This compound, or its related analogs, could be part of an antiviral strategy for preventing reinfection with HBV, including clinically relevant nucleos(t)ide analog-resistant virus.

IMPORTANCE:

For achieving better treatment and prevention of hepatitis B virus (HBV) infection, anti-HBV agents targeting a new molecule are in great demand. Although sodium taurocholate cotransporting polypeptide (NTCP) has recently been reported to be an essential host factor for HBV entry, there is a limited number of reports that identify new compounds targeting NTCP and inhibiting HBV entry. Here, from an uncharacterized chemical library, we isolated a structurally new compound, named vanitaracin A, which inhibited the process of entry of HBV and hepatitis D virus (HDV). This compound was suggested to directly interact with NTCP and inhibit its transporter activity. Importantly, vanitaracin A inhibited the entry of all HBV genotypes examined and of a clinically relevant nucleos(t)ide analog-resistant HBV isolate.

• Authors: Manabu Kaneko, Koichi Watashi, Shinji Kamisuki, Hiroki Matsunaga, Masashi Iwamoto, Fumihiro Kawai, Hirofumi Ohashi, Senko Tsukuda, Satomi Shimura, Ryosuke Suzuki, Hideki Aizaki, Masaya Sugiyama, Sam-Yong Park, Takayoshi Ito, Naoko Ohtani, Fumio Sugawara, Yasuhito Tanaka, Masashi Mizokami, Camille Sureau, Takaji Wakita
• Journal: Journal of virology (J Virol) Vol. 89 Issue 23 Pg. 11945-53 (Dec 2015) ISSN: 1098-5514 [Electronic] United States
• PMID: 26378168 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Chemical References

• DNA Primers
• Organic Anion Transporters, Sodium-Dependent
• Polyketides
• Small Molecule Libraries
• Symporters
• vanitaracin A
• sodium-bile acid cotransporter

Topics

• Cell Line
• DNA Primers (genetics)
• Drug Discovery (methods)
• Fluorescent Antibody Technique, Indirect
• Hepatitis B (drug therapy)
• Hepatitis B virus (physiology)
• Hepatitis Delta Virus (physiology)
• Humans
• Luminescent Measurements
• Organic Anion Transporters, Sodium-Dependent (metabolism)
• Polyketides (pharmacology)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Small Molecule Libraries
• Surface Plasmon Resonance
• Symporters (metabolism)
• Talaromyces (chemistry)
• Virus Internalization (drug effects)