The proposed project aims at developing a novel therapeutic intervention against chronic hepatitis B, which currently remains a significant public health challenge worldwide. We will explore the development of a group of newly identified compounds that inhibit the formation of hepatitis B virus (HBV) covalently closed circular (ccc) DNA, which is not targeted by current available antiviral medications. HBV cccDNA plays a central role in viral infection establishment and persistence, and is the basis for the failure of current antiviral treatments and virus rebound after the cessation of therapy. Therefore the elimination of cccDNA is the ultimate goal in curing HBV infection. Through our efforts to screen an 80,300 small molecule library using an innovative cell-based cccDNA high throughput assay, two structurally related disubstituted-sulfonamides (DSS) were discovered that have dramatic inhibition of cccDNA formation by interfering with the deproteinization of HBV genomic relaxed circular (rc) DNA, which serves as the intermediate precursor for cccDNA. To determine whether Investigational New Drug (IND)-enabling studies are justified, we plan to optimize these compounds, assess their utility against drug resistant infections and in combination with existing drugs in vitro, determine their in vivo characteristics and efficacy, and further study their mechanism of action. Successful completion of our goals will produce at least one new lead to advanced preclinical studies.

Public Health Relevance

Hepatitis B virus (HBV) infection is a severe public health problem affecting about 350 million individuals worldwide. Chronic hepatitis B patients have a high risk of occurrence of hepatocirrhosis and liver cancer. Currently approved drugs for treatment of chronic hepatitis B, including alpha interferon, and nucleos(t)ide analogues inhibiting the viral polymerase, are limited by poor response, side effects and emergence of drug resistance. In our proposal, we are aiming at the development of a non-classical anti-HBV agent with novel antiviral target. Our research is thus highly related to the public health interest. The accomplishment of proposed research will ultimately lead to the better therapeutic for the management of hepatitis B disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI094474-02
Application #
8262383
Study Section
Special Emphasis Panel (ZAI1-FDS-M (J2))
Program Officer
Koshy, Rajen
Project Start
2011-05-05
Project End
2016-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$627,419
Indirect Cost
$146,500
Name
Drexel University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Mitra, Bidisha; Guo, Haitao (2016) Hepatitis B virus X protein crosses out Smc5/6 complex to maintain covalently closed circular DNA transcription. Hepatology 64:2246-2249
Liu, Chunlan; Cai, Dawei; Zhang, Lin et al. (2016) Identification of hydrolyzable tannins (punicalagin, punicalin and geraniin) as novel inhibitors of hepatitis B virus covalently closed circular DNA. Antiviral Res 134:97-107
Cai, Dawei; Wang, Xiaohe; Yan, Ran et al. (2016) Establishment of an inducible HBV stable cell line that expresses cccDNA-dependent epitope-tagged HBeAg for screening of cccDNA modulators. Antiviral Res 132:26-37
Yan, Ran; Zhang, Yongmei; Cai, Dawei et al. (2015) Spinoculation Enhances HBV Infection in NTCP-Reconstituted Hepatocytes. PLoS One 10:e0129889
Jain, Surbhi; Chang, Ting-Tsung; Chen, Sitong et al. (2015) Comprehensive DNA methylation analysis of hepatitis B virus genome in infected liver tissues. Sci Rep 5:10478
Guo, Ju-Tao; Guo, Haitao (2015) Metabolism and function of hepatitis B virus cccDNA: Implications for the development of cccDNA-targeting antiviral therapeutics. Antiviral Res 122:91-100
Yan, Ran; Zhao, Xuesen; Cai, Dawei et al. (2015) The Interferon-Inducible Protein Tetherin Inhibits Hepatitis B Virus Virion Secretion. J Virol 89:9200-12
Zhang, Yongmei; Mao, Richeng; Yan, Ran et al. (2014) Transcription of hepatitis B virus covalently closed circular DNA is regulated by CpG methylation during chronic infection. PLoS One 9:e110442
Block, Timothy M; Gish, Robert; Guo, Haitao et al. (2013) Chronic hepatitis B: what should be the goal for new therapies? Antiviral Res 98:27-34
Mao, Richeng; Nie, Hui; Cai, Dawei et al. (2013) Inhibition of hepatitis B virus replication by the host zinc finger antiviral protein. PLoS Pathog 9:e1003494

Showing the most recent 10 out of 15 publications