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Antiviral Agents

Heat Stress Cognate 70 Host Protein as a Potential Drug Target against Drug Resistance in Hepatitis B Virus

Yu-Ping Wang, Fei Liu, Hong-Wei He, Yan-Xin Han, Zong-Gen Peng, Bao-Wei Li, Xue-Fu You, Dan-Qing Song, Zhuo-Rong Li, Li-Yan Yu, Shan Cen, Bin Hong, Chen-Heng Sun, Li-Xun Zhao, Barry Kreiswirth, David Perlin, Rong-Guang Shao, Jian-Dong Jiang
Yu-Ping Wang
1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
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Fei Liu
1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
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Hong-Wei He
1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
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Yan-Xin Han
1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
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Zong-Gen Peng
1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
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Bao-Wei Li
1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
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Xue-Fu You
1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
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Dan-Qing Song
1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
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Zhuo-Rong Li
1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
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Li-Yan Yu
1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
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Shan Cen
1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
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Bin Hong
1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
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Chen-Heng Sun
1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
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Li-Xun Zhao
1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
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Barry Kreiswirth
2Public Health Research Institute, Newark, New Jersey 07103
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David Perlin
2Public Health Research Institute, Newark, New Jersey 07103
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Rong-Guang Shao
1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
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Jian-Dong Jiang
1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
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  • For correspondence: jiang.jdong@163.com
DOI: 10.1128/AAC.01764-09
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ABSTRACT

Heat stress cognate 70 (Hsc70) is a host protein associated with hepatitis B virus (HBV) replication. The goal of this study was to investigate whether Hsc70 could be an anti-HBV drug target. Our results showed that introducing Hsc70 increased HBV replication in HBV+ human hepatocytes (HepG2.2.15 cells). The coiled-coil region on Hsc70 (nucleotides 1533 to 1608; amino acids 511 to 536) was the key sequence for HBV replication. Knockdown of Hsc70 expression by RNA interference (RNAi) largely inhibited HBV replication with no cytotoxicity to the host. Using an Hsc70 mRNA screening assay, the natural compound oxymatrine (OMTR) was found to be a selective inhibitor for Hsc70 expression. Then, OMTR was used to investigate the potential of Hsc70 as an anti-HBV drug target. OMTR inhibited Hsc70 mRNA expression by 80% and HBV DNA replication by over 60% without causing cytotoxicity. The anti-HBV effect of OMTR appeared to be mediated by destabilizing Hsc70 mRNA. The half-life (T1/2) of Hsc70 mRNA decreased by 50% in OMTR-treated hepatocytes. The Hsc70 mRNA 3′-untranslated-region (UTR) sequence was the element responsible for OMTR's destabilization activity. OMTR suppressed HBV de novo synthesis at the reverse transcription stage from pregenomic RNA (pgRNA) to DNA and was active against either wild-type HBV or strains resistant to lamivudine, adefovir, and entecavir. Therefore, host Hsc70 could be a novel drug target against HBV, and OMTR appears to inhibit HBV replication by destabilizing Hsc70 mRNA. As the target is not a viral protein, OMTR is active for either wild-type HBV or strains resistant to reverse transcriptase (RT) inhibitors.

  • Copyright © 2010 American Society for Microbiology
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Heat Stress Cognate 70 Host Protein as a Potential Drug Target against Drug Resistance in Hepatitis B Virus
Yu-Ping Wang, Fei Liu, Hong-Wei He, Yan-Xin Han, Zong-Gen Peng, Bao-Wei Li, Xue-Fu You, Dan-Qing Song, Zhuo-Rong Li, Li-Yan Yu, Shan Cen, Bin Hong, Chen-Heng Sun, Li-Xun Zhao, Barry Kreiswirth, David Perlin, Rong-Guang Shao, Jian-Dong Jiang
Antimicrobial Agents and Chemotherapy Apr 2010, 54 (5) 2070-2077; DOI: 10.1128/AAC.01764-09

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Heat Stress Cognate 70 Host Protein as a Potential Drug Target against Drug Resistance in Hepatitis B Virus
Yu-Ping Wang, Fei Liu, Hong-Wei He, Yan-Xin Han, Zong-Gen Peng, Bao-Wei Li, Xue-Fu You, Dan-Qing Song, Zhuo-Rong Li, Li-Yan Yu, Shan Cen, Bin Hong, Chen-Heng Sun, Li-Xun Zhao, Barry Kreiswirth, David Perlin, Rong-Guang Shao, Jian-Dong Jiang
Antimicrobial Agents and Chemotherapy Apr 2010, 54 (5) 2070-2077; DOI: 10.1128/AAC.01764-09
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KEYWORDS

Alkaloids
antiviral agents
drug design
HSC70 Heat-Shock Proteins
hepatitis B
hepatitis B virus
Quinolizines

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