Antivirals interacting with hepatitis B virus core protein and core mutations may misdirect capsid assembly in a similar fashion
Antivirals interacting with hepatitis B virus core protein and core mutations may misdirect capsid assembly in a similar fashion
复制标题
DOI：
10.1016/j.bcp.2003.08.001
复制
发表时间：
2003-12-15
影响因子：
5.8
通讯作者：
Schröder, CH
中科院分区：
文献类型：
--
作者：
Hacker, HJ;Deres, K;Schröder, CH
最近，杂芳基嘧啶（HAP）已被确定为有效的衣壳成熟抑制剂。在这里，我们讨论了HAP的作用模式比较野生型和突变体的核心蛋白的聚集表型与HAP或其他代理与核心蛋白相互作用的各自的表型。相关的测试包括核心融合蛋白介导的反式激活的双杂交系统和衣壳的形成。反式激活似乎不受HAP或阻止组装的突变的影响，这一发现令人惊讶，并提出了相互作用的杂交核心蛋白的结构问题：它们是单体，二聚体还是寡聚体？不排除核心融合单体的直接活性，但由于快速同源二聚化，认为极不可能。核心融合二聚体在反式激活中的作用将表明对HAP具有不同敏感性的不同相互作用。关于在双杂交系统中获得的数据的意义，谨慎是必要的，因为反式激活的位点是细胞核，而复制过程中核心蛋白相互作用的真实的位点是细胞质。显然，HAP使HBV核心蛋白的单体-单体界面不受影响，但通过与已知对二聚体多聚化和稳定衣壳形成至关重要的区域相互作用来防止衣壳成熟。建议使用抗病毒药物作为阐明基因组复制和衣壳组装早期步骤的工具。其框架可能是这样的假设：病毒使用可溶性核心蛋白，即HBeAg的细胞内成熟中间体，用于核心靶向自我限制复制。(C)2003年爱思唯尔公司All rights reserved.
Recently, heteroarylpyrimidines (HAP) have been identified as potent inhibitors of capsid maturation. Here we discuss the HAP mode of action comparing the aggregation phenotype of wild-type and mutant core proteins with the respective phenotype imposed by HAP or other agents interacting with core protein. Pertinent tests include core fusion protein-mediated transactivation in a two-hybrid system and capsid formation. The finding that transactivation appeared to be unaffected by HAP, or by mutations preventing assembly, is surprising and raises the question for the structure of the interacting hybrid core proteins: Are they monomers, dimers or even oligomers? A direct activity of core fusion monomers is not excluded but considered to be highly unlikely due to rapid homodimerisation. A role of core fusion dimers in transactivation would indicate distinct interactions with a differential sensitivity to HAP. Regarding significance of data gained in two-hybrid systems, caution is necessary, since the site of transactivation is the nucleus, whereas the real site of the core protein interactions during replication is the cytoplasm. Apparently, HAP leave the monomer-monomer interface of HBV core protein unaffected but prevent capsid maturation by interacting with a region known to be crucial for dimer multimerisation and formation of stable capsids. It is suggested to use antivirals as tools for the elucidation of early steps in genome replication and capsid assembly. A frame for this could be the hypothesis that the virus uses soluble core protein, namely intracellular maturation intermediates of HbeAg for a core targeted self-restriction of replication. (C) 2003 Elsevier Inc. All rights reserved.