β-Thujaplicinol inhibits hepatitis B virus replication by blocking the viral ribonuclease H activity
β-Thujaplicinol inhibits hepatitis B virus replication by blocking the viral ribonuclease H activity
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DOI：
10.1016/j.antiviral.2013.06.007
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发表时间：
2013-09-01
影响因子：
7.6
通讯作者：
Tavis, John E.
中科院分区：
文献类型：
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作者：
Hu, Yuan;Cheng, Xiaohong;Tavis, John E.
B型肝炎病毒（HBV）是一种嗜肝DNA病毒，通过逆转录进行复制。它每年慢性感染超过3.5亿人，并导致约100万患者死亡。治疗主要采用核苷（酸）类似物，其通过病毒逆转录酶很好地抑制病毒DNA合成，但很少治愈感染，因此需要额外的治疗。逆转录需要病毒核糖核酸酶H（RNAseH）在病毒RNA复制成DNA后将其破坏。我们最近生产了活性重组HBV RNAseH，并证明人类免疫缺陷病毒（HIV）RNAseH拮抗剂可以高频率抑制HBV酶。在这里，我们将这些结果扩展到β-thujaplicinol，一种抑制HIV RNAseH的羟基化托酚酮。在生化测定中，β-侧柏酚抑制HBV基因型D和H的RNAseH，IC 50值分别为5.9 +/- 0.7和2.3 +/- 1.7 μ M。它通过抑制RNAseH活性阻断HBV基因型A和D在培养物中的复制，估计EC 50约为5 μ M，CC 50为10.1 +/- 1.7 μ M。β-thujaplicinol对来自多种HBV基因型的RNAseH序列的活性意味着，如果可以鉴定出具有改善的功效和降低的毒性的β-thujaplicinol的化学衍生物，则它们将有希望作为抗HBV剂。(C)2013爱思唯尔有限公司版权所有。
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.