Hepatitis C (HCV) is a major cause of cirrhosis and considerable morbidity worldwide. Current therapy for chronic HCV infection is alpha-interferon (IFN) and ribavirin (RBV) for 24-48 weeks, together with an approved protease inhibitor, depending on HCV genotype. Unfortunately, about half of all treated patients fail to achieve sustained viral eradication after therapy. Intense research has focused on development of new direct-acting anti-HCV drugs to supplement and improve present therapy. Although the first generation of HCV protease inhibitors is a noticeable step forward, it is imperative that we continue to pursue new, more effective antivirals agents. Recent findings from our group and others indicate that precursors and products of heme metabolism are direct acting antiviral agents. Metalloporphyrins (MPs) such as heme and heme oxidation products such as biliverdin potently inhibit HCV NS3/4a protease. These exciting findings raise the possibility that MPs could be used as novel, yet natural antiviral therapeutic drugs for treatment of chronic HCV infection. As a group, MPs are inexpensive, have minimal toxicity, are easy to isolate and prepare, and are abundant in life. Some MPs such as heme and Zinc protoporphyrin have already been approved for selective therapeutic actions in humans such as the porphyrias and jaundice of the newborn. Mechanistically, our data indicate that specific MPs inactivate the NS3/4a protease across a broad virucidal spectrum of HCV genotypes. MPs also restore innate immune signaling for type I interferons after inhibition by viral protease suggesting that they will provide additional benefits for innate immune system recognition, host immunity, and viral clearance. The overall hypothesis of this application is that heme precursors and selective products of heme oxidation are potent inhibitors of the HCV NS3/4a protease. There are three Specific Aims: 1) We will characterize the anti-HCV NS3/4a protease activity of Metalloporphyrins in vitro. 2) We will study MP inhibition of HCV replication and MP intracellular activities in vitro and 3) Study the anti-HCV activities of metalloporphyrins in vivo. The long term goal of our work is to identify the best antiviral agents of this class of compounds such that we can improve treatment regimens for chronic HCV infection and reduce the medical and social burden of HCV end stage liver disease for US veterans. The immediate goals of this application are to characterize the antiviral actions of MPs as well as establish the feasibility of these compounds for therapeutic use in humans.

Public Health Relevance

Hepatitis C virus (HCV) is a major cause of cirrhosis and need for liver transplantation worldwide. The standard treatment for HCV is a combination of interferon and ribavirin which is only effective in about 50% of cases. This research project will facilitate development of a new and novel class of antiviral drugs that inhibit viral replication and life cycle. The goals of this project, if achieved, will certainly benefit millions of patients worldwide with chronic HCV infection.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000159-08
Application #
8974220
Study Section
Infectious Diseases A (INFA)
Project Start
2009-04-01
Project End
2017-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
8
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Iowa City VA Medical Center
Department
Type
DUNS #
028084333
City
Iowa City
State
IA
Country
United States
Zip Code
52246
Schmidt, Warren N; Nelson, David R; Pawlotsky, Jean-Michel et al. (2014) Direct-acting antiviral agents and the path to interferon independence. Clin Gastroenterol Hepatol 12:728-37
Kayali, Zeid; Schmidt, Warren N (2014) Finally sofosbuvir: an oral anti-HCV drug with wide performance capability. Pharmgenomics Pers Med 7:387-98
Zhu, Zhaowen; Mathahs, M Meleah; Schmidt, Warren N (2013) Restoration of type I interferon expression by heme and related tetrapyrroles through inhibition of NS3/4A protease. J Infect Dis 208:1653-63
Schmidt, Warren N; Mathahs, M Meleah; Zhu, Zhaowen (2012) Heme and HO-1 Inhibition of HCV, HBV, and HIV. Front Pharmacol 3:129
Bandyopadhyay, Sarmistha; Friedman, Robin C; Marquez, Rebecca T et al. (2011) Hepatitis C virus infection and hepatic stellate cell activation downregulate miR-29: miR-29 overexpression reduces hepatitis C viral abundance in culture. J Infect Dis 203:1753-62
Poynard, Thierry; Munteanu, Mona; Colombo, Massimo et al. (2011) FibroTest is an independent predictor of virologic response in chronic hepatitis C patients retreated with pegylated interferon alfa-2b and ribavirin in the EPICĀ³ program. J Hepatol 54:227-35
Marquez, Rebecca T; Bandyopadhyay, Sarmistha; Wendlandt, Erik B et al. (2010) Correlation between microRNA expression levels and clinical parameters associated with chronic hepatitis C viral infection in humans. Lab Invest 90:1727-36
Zhu, Zhaowen; Wilson, Anne T; Luxon, Bruce A et al. (2010) Biliverdin inhibits hepatitis C virus nonstructural 3/4A protease activity: mechanism for the antiviral effects of heme oxygenase? Hepatology 52:1897-905
Ali, Sobia; Stolpen, Alan H; Schmidt, Warren N (2010) Portosystemic encephalopathy due to mesoiliac shunt in a patient without cirrhosis. J Clin Gastroenterol 44:381-3
Zhu, Zhaowen; Wilson, Anne T; Gopalakrishna, Kota et al. (2010) Hepatitis C virus core protein enhances Telomerase activity in Huh7 cells. J Med Virol 82:239-48

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