Hepatitis B virus genetic diversity has minimal impact on sensitivity of the viral ribonuclease H to inhibitors.
Hepatitis B virus genetic diversity has minimal impact on sensitivity of the viral ribonuclease H to inhibitors.
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DOI：
10.1016/j.antiviral.2016.09.009
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发表时间：
2016-11
影响因子：
7.6
通讯作者：
Tavis, John E.
中科院分区：
文献类型：
--
作者：
Lu, Gaofeng;Villa, Juan Antonio;Donlin, Maureen J.;Edwards, Tiffany C.;Cheng, Xiaohong;Heier, Richard F.;Meyers, Marvin J.;Tavis, John E.
B型肝炎病毒（HBV）可引起肝炎、肝硬化、肝功能衰竭和肝癌，但目前使用核苷（酸）类似物或（聚乙二醇化）干扰素α的治疗方法不能清除大多数患者的感染。以生产抗HBV药物为目标而开发的HBV核糖核酸酶H（RNaseH）抑制剂是与核苷（酸）类似物组合使用以提高治疗功效的有希望的候选物。HBV在遗传上非常多样，至少有8种基因型在序列水平上差异≥8%。这种多样性反映在病毒RNaseH酶中，提高了不同HBV基因型或分离株对RNaseH抑制剂敏感性不同的可能性。为了评估这种可能性，我们表达并纯化了来自基因型B、C和D的18种患者来源的RNaseH。评估了基础RNaseH活性和对来自三种不同化学型的三种新型RNaseH抑制剂的敏感性。我们还评估了四种共有HBV RNA酶H，以确定这些序列是否适用于抗病毒药物筛选。患者来源的酶在其基础RNaseH活性方面变化超过10倍，但它们对三种抑制剂中的每一种都具有同等的敏感性。类似地，所有四种共有HBV RNaseH酶都是活性的，并且对RNaseH抑制剂同样敏感。这些数据表明，广泛的RNaseH序列将适用于抗病毒药物筛选，并且基因型或分离株特异性遗传变异不太可能在抗HBV RNaseH的抗病毒药物开发过程中存在障碍。
Hepatitis 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.
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