Trapping of hepatitis B virus capsid assembly intermediates by phenylpropenamide assembly accelerators.
Trapping of hepatitis B virus capsid assembly intermediates by phenylpropenamide assembly accelerators.
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DOI：
10.1021/cb100275b
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发表时间：
2010-12-17
影响因子：
4
通讯作者：
Zlotnick, Adam
中科院分区：
文献类型：
--
作者：
Katen, Sarah P.;Chirapu, Srinivas Reddy;Finn, M. G.;Zlotnick, Adam
了解病毒衣壳的生物自组装过程是了解病毒生命周期的关键，也是设计基于组装的抗病毒药物的平台。在这里，我们鉴定和表征了苯丙烯酰胺小分子家族，已知在体内具有抗病毒活性，作为乙肝病毒(乙肝病毒)衣壳的组装效应器。我们发现两个具有代表性的苯丙烯酰胺类化合物是组装促进剂，提高了组装速度，但仅略微增加了乙肝病毒衣壳的稳定性；这些数据为它们的抗病毒活性提供了物理化学基础。与之前描述的乙肝病毒组装效应器不同，苯丙烯酰胺不会错误地引导组装；相反，加速的反应会继续进行，从而产生形态正常的衣壳。然而，在苯基丙烯酰胺存在的情况下，衣壳组装的特征是组装中间体的动力学捕获。这些陷阱在接近生理的条件下分解，但在有利于苯丙烯酰胺结合和强烈的核心蛋白质-蛋白质相互作用的条件下，我们发现捕获的中间产物持续存在。苯基丙烯酰胺通过捕获路径上的组装中间产物作为乙肝病毒衣壳组装途径的化学探针，说明了反应动力学对衣壳组装的主导影响。
Understanding the biological self-assembly process of virus capsids is key to understanding the viral life cycle, as well as serving as a platform for the design of assembly-based antiviral drugs. Here we identify and characterize the phenylpropenamide family of small molecules, known to have antiviral activity in vivo, as assembly effectors of the Hepatitis B Virus (HBV) capsid. We have found two representative phenylpropenamides to be assembly accelerators, increasing the rate of assembly with only modest increases in the stability of the HBV capsids; these data provide a physical-chemical basis for their antiviral activity. Unlike previously described HBV assembly effectors, the phenylpropenamides do not misdirect assembly; rather, the accelerated reactions proceed on-path to produce morphologically normal capsids. However, capsid assembly in the presence of phenylpropenamides is characterized by kinetic trapping of assembly intermediates. These traps resolve under conditions close to physiological, but under conditions which favor phenylpropenamide binding and strong core protein-protein interactions, we found that trapped intermediates persist. The phenylpropenamides serve as chemical probes of the HBV capsid assembly pathway by trapping on-path assembly intermediates, illustrating the governing influence of reaction kinetics on capsid assembly.
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影响因子：
2.9
作者：
Ceres, P;Zlotnick, A
通讯作者：
Zlotnick, A
影响因子：
5.6
作者：
Freund, Stefan M. V.;Johnson, Christopher M.;Ferguson, Neil
通讯作者：
Ferguson, Neil
影响因子：
7.6
作者：
Feld, J. J.;Colledge, D.;Locarnini, S. A.
通讯作者：
Locarnini, S. A.
影响因子：
56.9
作者：
Deres, K;Schröder, CH;Rübsamen-Waigmann, H
通讯作者：
Rübsamen-Waigmann, H
DOI：
10.1083/jcb.145.1.45
发表时间：
1999-04-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kann M;Sodeik B;Vlachou A;Gerlich WH;Helenius A
通讯作者：
Helenius A