Journal article
Biliverdin Inhibits Hepatitis C Virus Nonstructural 3/4A Protease Activity: Mechanism for the Antiviral Effects of Heme Oxygenase?
Hepatology (Baltimore, Md.), Vol.52(6), pp.1897-1905
2010
DOI: 10.1002/hep.23921
PMID: 21105106
Abstract
Induction of heme oxygenase‐1 (HO‐1) inhibits hepatitis C virus (HCV) replication. Of the products of the reaction catalyzed by HO‐1, iron has been shown to inhibit HCV ribonucleic acid (RNA) polymerase, but little is known about the antiviral activity of biliverdin (BV). Herein, we report that BV inhibits viral replication and viral protein expression in a dose‐dependent manner in replicons and cells harboring the infectious J6/JFH construct. Using the SensoLyte 620 HCV Protease Assay with a wide wavelength excitation/emission (591 nm/622 nm) fluorescence energy transfer peptide, we found that both recombinant and endogenous nonstructural 3/4A (NS3/4A) protease from replicon microsomes are potently inhibited by BV. Of the tetrapyrroles tested, BV was the strongest inhibitor of NS3/4A activity, with a median inhibitory concentration (IC50) of 9 μM, similar to that of the commercial inhibitor, AnaSpec (Fremont, CA) #25346 (IC50 5 μM). Lineweaver‐Burk plots indicated mixed competitive and noncompetitive inhibition of the protease by BV. In contrast, the effects of bilirubin (BR) on HCV replication and NS3/4A were much less potent. Because BV is rapidly converted to BR by biliverdin reductase (BVR) intracellularly, the effect of BVR knockdown on BV antiviral activity was assessed. After greater than 80% silencing of BVR, inhibition of viral replication by BV was enhanced. BV also increased the antiviral activity of α‐interferon in replicons. Conclusion: BV is a potent inhibitor of HCV NS3/4A protease, which likely contributes to the antiviral activity of HO‐1. These findings suggest that BV or its derivatives may be useful in future drug therapies targeting the NS3/4A protease.
Details
- Title: Subtitle
- Biliverdin Inhibits Hepatitis C Virus Nonstructural 3/4A Protease Activity: Mechanism for the Antiviral Effects of Heme Oxygenase?
- Creators
- Zhaowen Zhu - Department of Internal Medicine and Research Service, Veterans Administration Medical Center, Iowa City, IA, United StatesAnne T WILSON - Department of Internal Medicine of the Roy G. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, United StatesBruce A LUXON - Department of Internal Medicine of the Roy G. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, United StatesKyle E BROWN - Department of Internal Medicine and Research Service, Veterans Administration Medical Center, Iowa City, IA, United StatesM Meleah Mathahs - Department of Internal Medicine and Research Service, Veterans Administration Medical Center, Iowa City, IA, United StatesSarmistha BANDYOPADHYAY - Department of Internal Medicine of the Roy G. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, United StatesAnton P MCCAFFREY - Department of Internal Medicine of the Roy G. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, United StatesWarren N SCHMIDT - Department of Internal Medicine and Research Service, Veterans Administration Medical Center, Iowa City, IA, United States
- Resource Type
- Journal article
- Publication Details
- Hepatology (Baltimore, Md.), Vol.52(6), pp.1897-1905
- Publisher
- Wiley; Hoboken, NJ
- DOI
- 10.1002/hep.23921
- PMID
- 21105106
- ISSN
- 0270-9139
- eISSN
- 1527-3350
- Language
- English
- Date published
- 2010
- Academic Unit
- Dermatology; Gastroenterology and Hepatology; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984047726602771
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