乙型肝炎病毒遗传多样性对病毒核糖核酸酶H对抑制剂的敏感

StephenW

Antiviral Res. 2016 Sep 28;135:24-30. 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 MJ2, Edwards TC2, Cheng X2, Heier RF3, Meyers MJ3, Tavis JE4.
Author information

• 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 Elsevier B.V. All rights reserved.

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

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

StephenW

抗病毒研究2016 Sep 28; 135：24-30。 doi：10.1016 / j.antiviral.2016.09.009。 [打印前的电子版]
乙型肝炎病毒遗传多样性对病毒核糖核酸酶H对抑制剂的敏感性具有最小的影响。
Lu G1，Villa JA2，Donlin MJ2，Edwards TC2，Cheng X2，Heier RF3，Meyers MJ3，Tavis JE4。
作者信息

    摘要：目的探讨分子微生物学和免疫学的研究进展。郑州大学第二附属医院消化内科，河南郑州，中华人民共和国。
    2分子微生物学和免疫学和圣路易斯大学肝脏中心，圣路易斯大学医学院，圣路易斯，密苏里州，美国。
    3世界卫生和医学中心，圣路易斯大学医学院，圣路易斯，密苏里州，美国。
    4分子微生物学和免疫学和圣路易斯大学肝脏中心，圣路易斯大学医学院，圣路易斯，密苏里州，美国。电子地址：[email protected]。

抽象

乙型肝炎病毒（HBV）引起肝炎，肝硬化，肝衰竭和肝癌，但目前使用nucelos（t）ide类似物或（聚乙二醇化）干扰素α的治疗在大多数患者中不能清除感染。为了产生抗HBV药物而开发的HBV核糖核酸酶H（RNaseH）的抑制剂是与核苷（类似物）组合用于改善治疗功效的有希望的候选物。 HBV在遗传上非常多样化，具有至少8种在序列水平上相差≥8％的基因型。这种多样性反映在病毒RNA酶H酶中，提高了不同的HBV基因型或分离物可能对RNaseH抑制剂具有不同的敏感性的可能性。为了评估这种可能性，我们从基因型B，C和D表达和纯化18病人派生RNaseHs。评估基底核糖核酸酶活性和三个不同化学型的三个新型RNaseH抑制剂的敏感性。我们还评估了四种共有HBV核糖核酸酶，以确定这样的序列是否适合用于抗病毒药物筛选。患者来源的酶在其基底RNA酶H活性方面变化超过10倍，但它们对三种抑制剂中的每一种同等地敏感。类似地，所有四种共有HBV RNA酶H具有活性，并且对RNaseH抑制剂同样敏感。这些数据表明，宽范围的RNaseH序列将适合用于抗病毒药物筛选，并且基因型或分离物特异性遗传变异在针对HBV RNaseH的抗病毒药物开发期间不可能呈现屏障。

版权所有©2016 Elsevier B.V.保留所有权利。
关键词：

DNA病毒;遗传多样性;乙型肝炎病毒;核糖核酸酶H.

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

tonychant

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四十己过

把一些垃圾文章顶到第二页面去，版主跑哪去了？