Hepatitis B virus reverse transcriptase - Target of current antiviral therapy and future drug development.
Hepatitis B virus reverse transcriptase - Target of current antiviral therapy and future drug development.
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DOI：
10.1016/j.antiviral.2015.09.011
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发表时间：
2015-11
影响因子：
7.6
通讯作者：
Hu J
中科院分区：
文献类型：
--
作者：
Clark DN;Hu J
B型肝炎病毒（HBV）感染依赖于病毒聚合酶的正常功能，聚合酶是一种具有多种活性的专门逆转录酶（RT）。目前批准的所有用于治疗慢性B型肝炎病毒的抗病毒药物，除干扰素外，都靶向RT，属于同一化学类别-它们都是核苷类似物。病毒DNA合成通过RT酶在几个不同的步骤中进行，每个步骤具有不同的RT构象要求。原则上，每个阶段都可以由不同的抗病毒药物靶向。特别是，HBV RT具有独特的能力，在新的蛋白引发反应中使用其自身作为蛋白引物来启动病毒DNA合成。为了帮助识别RT抑制剂并研究其作用机制，已经开发了许多实验系统，每个系统在分子水平上解剖蛋白质引发和病毒DNA合成反应的后续阶段的能力各不相同。迄今为止最有效的两种药物，恩替卡韦和替诺福韦，可以抑制蛋白质引发和随后的HBV DNA合成的DNA延伸阶段。有趣的是，clevudine，一种胸苷类似物，可以以非竞争性方式抑制蛋白质引发和DNA延伸，而不被掺入病毒DNA中。因此，核苷RT抑制剂（NRTI）在抑制HBV RT方面可以在功能上模拟非NRTI（NNRTI）。因此，可以开发新的NRTI以及NNRTI来抑制HBV RT的DNA合成活性。此外，RT的其他活性也是HBV复制所必需的，包括特异性识别病毒RNA及其包装成病毒核衣壳，可以用于抗病毒药物的开发。为了更有效地抑制病毒复制并最终治愈慢性HBV感染，下一代抗HBV治疗可能需要包括NRTI、NNRTI和其他靶向病毒RT的药物以及其他病毒和宿主因子的各种组合。这篇文章是抗病毒研究专题讨论会的一部分，主题是“一个未完成的故事：从澳大利亚抗原的发现到B型肝炎新治疗方法的发展”。"
Hepatitis B virus (HBV) infections rely on the proper functioning of the viral polymerase enzyme, a specialized reverse transcriptase (RT) with multiple activities. All currently approved antiviral drugs for the treatment of chronic hepatitis B virus, except for interferon, target the RT and belong to the same chemical class - they are all nucleoside analogs. Viral DNA synthesis is carried out by the RT enzyme in several different steps, each with distinct RT conformational requirements. In principle, each stage may be targeted by distinct antiviral drugs. In particular, the HBV RT has the unique ability to initiate viral DNA synthesis using itself as a protein primer in a novel protein priming reaction. In order to help identify RT inhibitors and study their mechanisms of action, a number of experimental systems have been developed, each varying in its ability to dissect the protein priming and the subsequent stages of viral DNA synthesis reaction at the molecular level. Two of the most effective drugs to date, entecavir and tenofovir, can inhibit both the protein priming and the subsequent DNA elongation stages of HBV DNA synthesis. Interestingly, clevudine, a thymidine analog, can inhibit both protein priming and DNA elongation in a non-competitive manner and without being incorporated into the viral DNA. Thus, a nucleoside RT inhibitor (NRTI) can functionally mimic a non-NRTI (NNRTI) in its inhibition of the HBV RT. Therefore, novel NRTIs as well as NNRTIs may be developed to inhibit the DNA synthesis activity of the HBV RT. Furthermore, additional activities of the RT that are also essential to HBV replication, including specific recognition of the viral RNA and its packaging into viral nucleocapsids, may be exploited for antiviral development. To achieve a more potent inhibition of viral replication and ultimately cure chronic HBV infection, the next generation of anti-HBV therapies will likely need to include NRTIs, NNRTIs, and other agents that target the viral RT as well as other viral and host factors in various combinations. This article forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B."