BAY 41-4109 has multiple effects on Hepatitis B virus capsid assembly
BAY 41-4109 has multiple effects on Hepatitis B virus capsid assembly
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DOI：
10.1002/jmr.801
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发表时间：
2006-11-01
影响因子：
2.7
通讯作者：
Zlotnick, Adam
中科院分区：
文献类型：
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作者：
Stray, Stephen J.;Zlotnick, Adam
在这里，我们报告的效果杂芳基二氢嘧啶（HAP）抗病毒化合物，BAY 41-4109，对B肝炎病毒（HBV）衣壳组装和预制的HBV衣壳。HBV衣壳是120个衣壳蛋白二聚体的二十面体复合物。BAY 41 -4109通过靶向病毒衣壳的机制抑制体内病毒产生。我们发现BAY 41-4109能够在体外加速和误导衣壳组装。每五个HBV二聚体中只有一个HAP分子就足以诱导非衣壳聚合物的形成。与相关分子HAP-1（Stray等人，Proc. Natl. Acad. Sci. USA 102：813843，2005），在与BAY 41-4109的组装反应中没有观察到稳定的组装中间体，表明BAY 41-4109的加速组装仍然受成核速率的动力学调节。预形成的衣壳通过BAY 41-4109稳定，最高达每两个二聚体一个抑制剂分子的比例。然而，在BAY 41-4109：二聚体比率为1：1和更大时，衣壳被去稳定化以产生非常大的非衣壳聚合物。这些数据表明存在两个功能上可区分的药物结合位点的HBV衣壳。第一类位点的占据使衣壳稳定，而在第二类位点的结合需要或诱导在不使衣壳不稳定的情况下不能耐受的结构变化。我们的数据表明，HAP化合物可以通过诱导组装不适当地抑制病毒复制，当过量时，通过误导组装降低正常衣壳的稳定性。版权所有（c）2006约翰威利父子有限公司。
Here we report the effect of a heteroaryldihydropyrimidine (HAP) antiviral compound, BAY 41-4109, on Hepatitis B virus (HBV) capsid assembly and on preformed HBV capsids. The HBV capsid is an icosahedral complex of 120 capsid protein dimers. BAY41-4109 inhibits virus production in vivo by a mechanism that targets the viral capsid. We found that BAY 41-4109 was able to both accelerate and misdirect capsid assembly in vitro. As little as one HAP molecule for every five HBV dimers was sufficient to induce formation of non-capsid polymers. Unlike the related molecule HAP-1 (Stray et al., Proc. Natl. Acad. Sci. USA 102:813843, 2005), no stable assembly intermediates were observed in assembly reactions with BAY 41-4109, indicating that accelerated assembly by BAY 41-4109 was still kinetically regulated by the nucleation rate. Preformed capsids were stabilized by BAY 41-4109, up to a ratio of one inhibitor molecule per two dimers. However, at BAY 41-4109:dimer ratios of 1:1 and greater, capsids were destabilized to yield very large noncapsid polymers. These data suggest the existence of two functionally distinguishable classes of drug-binding sites on HBV capsids. Occupation of the first class of site stabilizes capsid, while binding at the second class requires or induces structural changes that cannot be tolerated without destabilizing the capsid. Our data suggest that HAP compounds may inhibit virus replication by inducing assembly inappropriately and, when in excess, by misdirecting assembly decreasing the stability of normal capsids. Copyright (c) 2006 John Wiley & Sons, Ltd.