乙肝病毒遗传多样性对病毒核糖核酸酶H对抑制剂的敏感性的

StephenW

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        Antiviral Res. 2016 Sep 28. pii: S0166-3542(16)30360-6. doi: 10.1016/j.antiviral.2016.09.009. [Epub ahead of print]
Hepatitis B virus genetic diversity has minimal impact on sensitivity of the viral ribonuclease H to inhibitors.Lu G1, Villa JA2, Donlin M2, Edwards TC2, Cheng X2, Heier RF3, Meyers MJ3, Tavis JE4.
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• 1Department of Molecular Microbiology and Immunology and Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, MO, USA; Department of Gastroenterology, The Second Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan, People's Republic of China.
• 2Department of Molecular Microbiology and Immunology and Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, MO, USA.
• 3Center for World Health and Medicine, Saint Louis University School of Medicine, St. Louis, MO, USA.
• 4Department of Molecular Microbiology and Immunology and Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, MO, USA. Electronic address: [email protected].
  

AbstractHepatitis B virus (HBV) causes hepatitis, cirrhosis, liver failure, and liver cancer, but the current therapies that employ either nucelos(t)ide analogs or (pegylated)interferon α do not clear the infection in the large majority of patients. Inhibitors of the HBV ribonuclease H (RNaseH) that are being developed with the goal of producing anti-HBV drugs are promising candidates for use in combination with the nucleos(t)ide analogs to improve therapeutic efficacy. HBV is genetically very diverse, with at least 8 genotypes that differ by ≥8% at the sequence level. This diversity is reflected in the viral RNaseH enzyme, raising the possibility that divergent HBV genotypes or isolates may have varying sensitivity to RNaseH inhibitors. To evaluate this possibility, we expressed and purified 18 patient-derived RNaseHs from genotypes B, C, and D. Basal RNaseH activity and sensitivity to three novel RNaseH inhibitors from three different chemotypes were assessed. We also evaluated four consensus HBV RNaseHs to determine if such sequences would be suitable for use in antiviral drug screening. The patient-derived enzymes varied by over 10-fold in their basal RNaseH activities, but they were equivalently sensitive to each of the three inhibitors. Similarly, all four consensus HBV RNaseH enzymes were active and were equally sensitive to an RNaseH inhibitor. These data indicate that a wide range of RNaseH sequences would be suitable for use in antiviral drug screening, and that genotype- or isolate-specific genetic variations are unlikely to present a barrier during antiviral drug development against the HBV RNaseH.
Copyright © 2016. Published by Elsevier B.V.


KEYWORDS: DNA virus; Genetic diversity; Hepatitis B virus; Ribonuclease H

PMID:27693161DOI:10.1016/j.antiviral.2016.09.009
[PubMed - as supplied by publisher]

StephenW

抗病毒水库。 2016年28月PII：S0166-3542（16）30360-6。 DOI：10.1016 / j.antiviral.2016.09.009。 [打印EPUB提前]
乙肝病毒遗传多样性对病毒核糖核酸酶H对抑制剂的敏感性的影响微乎其微。
鲁G1，别墅JA2，唐林M2，爱德华兹TC2，程X2，黑尔RF3，迈尔斯MJ3，塔维斯JE4。
作者信息

    分子微生物学和免疫学和圣路易斯大学肝病中心，医学圣路易斯大学医学院，圣路易斯，密苏里州，美国教研室;消化内科，第二附属医院，郑州大学，郑州，河南，中国人民共和国的部门。
    分子微生物学和免疫学和圣路易斯大学肝病中心，医学圣路易斯大学医学院，圣路易斯，密苏里州，美国的教研室。
    3Center世界卫生和医学，医学圣路易斯大学医学院，圣路易斯，密苏里州，美国。
    分子微生物学和免疫学和圣路易斯大学肝病中心，医学圣路易斯大学医学院，圣路易斯，密苏里州，美国4Department。电子地址：[email protected]。

抽象

乙型肝炎病毒（HBV）导致肝炎，肝硬化，肝功能衰竭，以及肝癌，但采用任nucelos（）类似物或（聚乙二醇化）干扰素α的当前疗法不会在大多数患者清除感染。正在以产生抗HBV药物的目标开发的乙肝病毒核糖核酸酶H（RNA酶H）的抑制剂是有希望的候选组合使用与核苷（酸）类似物，以提高治疗功效。乙肝病毒在遗传上是非常多样化的，与在序列一级≥8％，相差至少8个基因型。这种多样性是反映在病毒RNA酶H酶，提高的发散HBV基因型或株可以具有不同的敏感性RNA酶H抑制剂的可能性。为了评估这种可能性，我们表达并从基因型B，C和D基底RNA酶H活性，并从三个不同的化学型三种新型RNA酶H抑制剂灵敏度纯化的18患者来源RNaseHs进行了评估。我们还评估了4共识HBV RNaseHs确定这样的序列将是适用于抗病毒药物筛选中使用。的患者来源的酶通过在其基部RNA酶H活性10倍变化，但他们对每三个抑制剂的等效敏感。同样，所有四个共识HBV RNA酶H酶活跃，是一种RNA酶H抑制剂同样敏感。这些数据表明，广泛RNA酶H的序列将是适用于抗病毒药物筛选的使用，并且该基因型或特定隔离遗传变异不大可能抗病毒药物开发对乙肝病毒RNA酶H期间呈现的一个障碍。

版权所有©2016年出版由Elsevier B.V.
关键词：

DNA病毒;遗传多样性;乙型肝炎病毒;核糖核酸酶H

结论：
    27693161
DOI：
    10.1016 / j.antiviral.2016.09.009