The phenylpropenamide derivative AT-130 blocks HBV replication at the level of viral RNA packaging
The phenylpropenamide derivative AT-130 blocks HBV replication at the level of viral RNA packaging
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DOI：
10.1016/j.antiviral.2007.06.014
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发表时间：
2007-11-01
影响因子：
7.6
通讯作者：
Locarnini, S. A.
中科院分区：
文献类型：
--
作者：
Feld, J. J.;Colledge, D.;Locarnini, S. A.
核糖核酸(T)类似物抗病毒治疗慢性乙型肝炎已被证明在短期内有效，但耐药性的频繁发展限制了其临床应用。为了开发改进的联合疗法，需要针对病毒复制的其他阶段的药物。苯基丙烯酰胺衍生物AT-61和AT-130已被证明在体外可以抑制乙肝病毒的复制，但这些化合物的作用机制尚不清楚。本研究的目的是确定AT-130在几种体外复制模型中的作用机制。AT-130是一种非核苷类乙肝病毒抑制剂。这些研究发现，AT-130抑制了肝癌细胞中的HBVDNA复制，但对病毒DNNA聚合酶活性或核心蛋白翻译没有影响。在药物存在的情况下，HBVRNA的总产量也没有受到影响，而包裹的RNA的数量显著减少，从而抑制了随后的病毒逆转录。这些研究证实，在病毒封装和包装水平上通过非核苷类似物抑制乙肝病毒基因组复制是未来治疗慢性乙肝的治疗药物开发的潜在有用策略。(C)2007爱思唯尔公司保留所有权利。
Nucleos(t)ide analogue antiviral therapy for chronic hepatitis B has proven to be effective in the short term but the frequent development of resistance limits its clinical utility. Agents targeting other stages of viral replication are needed in order to develop improved combination therapies. The phenylpropenamide derivatives AT-61 and AT-130 have been shown to inhibit HBV replication in vitro, but the mechanism of action of these compounds remains undefined. The aim of this study was to determine the mechanism of action of AT-130, a non-nucleoside inhibitor of HBV in several in vitro models of replication. These studies found that AT-130 inhibited HBV DNA replication in hepatoma cells but had no effect on viral DNNA polymerase activity or core protein translation. Total HBV RNA production was also unaffected in the presence of the drug whilst the amount of encapsidated RNA was significantly reduced, thereby inhibiting subsequent viral reverse transcription. These studies have established that the inhibition of HBV genome replication by a non-nucleoside analogue acting at the level of viral encapsidation and packaging is a potentially useful strategy for future therapeutic drug development in the management of chronic hepatitis B. (C) 2007 Elsevier B.V. All rights reserved.