Cognate 70 Protein as a Potential Drug Target

StephenW

<http://aac.asm.org/cgi/content/abstract/54/5/2070>

Antimicrobial Agents and Chemotherapy, May 2010, p. 2070-2077, Vol. 54, No. 5
0066-4804/10/$12.00+0    doi:10.1128/AAC.01764-09
Copyright © 2010, American Society for Microbiology. All Rights Reserved.


Heat Stress Cognate 70 Host Protein as a Potential Drug Target against Drug
Resistance in Hepatitis B Virus
  , ,
Yu-Ping Wang,1, Fei Liu,1, Hong-Wei He,1, Yan-Xin Han,1 Zong-Gen Peng,1
Bao-Wei Li,1 Xue-Fu You,1 Dan-Qing Song,1 Zhuo-Rong Li,1 Li-Yan Yu,1 Shan
Cen,1 Bin Hong,1 Chen-Heng Sun,1 Li-Xun Zhao,1 Barry Kreiswirth,2 David
Perlin,2 Rong-Guang Shao,1 and Jian-Dong Jiang1*

Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences,
Beijing 100050, China,1 Public Health Research Institute, Newark, New Jersey
071032

Received 13 December 2009/ Returned for modification 15 January 2010/ Accepted
12 February 2010


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.

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* Corresponding author. Mailing address: Institute of Medicinal Biotechnology,
Chinese Academy of Medical Sciences, Beijing 100050, China. Phone:
86-10-63165290. Fax: 86-10-63017302. E-mail: [email protected]
Published ahead of print on 22 February 2010.
Supplemental material for this article may be found at http://aac.asm.org/.
The authors have paid a fee to allow immediate free access to this article.
Y.-P.W., F.L., and H.-W.H. made equal contributions to the work.

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Antimicrobial Agents and Chemotherapy, May 2010, p. 2070-2077, Vol. 54, No. 5
0066-4804/10/$12.00+0    doi:10.1128/AAC.01764-09
Copyright © 2010, American Society for Microbiology. All Rights Reserved



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