期刊
ANTIVIRAL RESEARCH
卷 99, 期 3, 页码 221-229出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.antiviral.2013.06.007
关键词
Hepatitis B virus; Reverse transcription; Ribonuclease H; beta-Thujaplicinol
资金
- Chongqing Medical University International Scholar award
- National Sciences Foundation of China award [NSFC 81101310]
- Research Fund for the Doctoral Program of Higher Education of China award [20115503120001]
- Major Projects of Chongqing Science and Technology award [CSTC2013jcyJC1002]
- National Science and Technology Major Project of China [2013ZX10002002]
- Saint Louis University School of Medicine President's Research Fund award
- Saint Louis University Molecular Microbiology and Immunology seed grant
- Friends of the Saint Louis University Liver Center seed grant
Hepatitis B virus (HBV) is a hepatotropic DNA virus that replicates by reverse transcription. It chronically infects >350 million people and kills about 1 million patients annually. Therapy primarily employs nucleos(t)ide analogs that suppress viral DNA synthesis by the viral reverse transcriptase very well but that rarely cure the infection, so additional therapies are needed. Reverse transcription requires the viral ribonuclease H (RNAseH) to destroy the viral RNA after it has been copied into DNA. We recently produced active recombinant HBV RNAseH and demonstrated that Human Immunodeficiency Virus (HIV) RNAseH antagonists could inhibit the HBV enzyme at a high frequency. Here, we extended these results to beta-thujaplicinol, a hydroxylated tropolone which inhibits the HIV RNAseH. beta-Thujaplicinol inhibited RNAseHs from HBV genotype D and H in biochemical assays with IC50 values of 5.9 +/- 0.7 and 2.3 +/- 1.7 mu M, respectively. It blocked replication of HBV genotypes A and D in culture by inhibiting the RNAseH activity with an estimated EC50 of similar to 5 mu M and a CC50 of 10.1 +/- 1.7 mu M. Activity of beta-thujaplicinol against RNAseH sequences from multiple HBV genotypes implies that if chemical derivatives of beta-thujaplicinol with improved efficacy and reduced toxicity can be identified, they would have promise as anti-HBV agents. (C) 2013 Elsevier B.V. All rights reserved.
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