Hayashi Kyoko, Hayashi Toshimitsu, Lee Jung-Bum
Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama, Japan.
Yakugaku Zasshi. 2010 Feb;130(2):171-6. doi: 10.1248/yakushi.130.171.
The limited efficacy and significant clinical toxicity of combination interferone and ribavirin therapy have generated strong interest in developing novel inhibitors of hepatitis C virus (HCV) replication. Recently, a growing understanding of the structure and function of critical viral enzymes and the development of HCV replicons have accelerated the development of highly specific candidate antiviral agents. In the life cycle of HCV, enveloped virions bind and penetrate into host cell using viral envelope glycoproteins. In the cytoplasm, the viral RNA genome serves as mRNA, and produces viral protein as a long polyprotein that is cleaved by both host and viral proteases. Progeny virions assemble by budding into ER/Golgi apparatus, where the glycoproteins maturate, and are released at the cell surface. All stages of replication cycle from the attachment of virus to the release of progeny should be antiviral targets. We have searched for antiviral candidates from natural resources for about 20 years. So far, we have found several classes of compounds with unique antiviral action. Among them, anionic substances interfere with virus attachment and/or entry, several substances inhibit the maturation of virus-specific glycoproteins, low molecules can inhibit the virus release from infected cells, glycerol derivatives reduce the pathogenicity of virus, and some compounds exert virucidal action that impairs the ability of virus to infect host cells. These substances might be worthy to be evaluated as novel anti-HCV agents by using HCV replication systems in cultured cell lines.
干扰素与利巴韦林联合治疗的疗效有限且临床毒性显著,这激发了人们对开发新型丙型肝炎病毒(HCV)复制抑制剂的浓厚兴趣。最近,对关键病毒酶的结构和功能的深入了解以及HCV复制子的发展加速了高特异性候选抗病毒药物的开发。在HCV的生命周期中,包膜病毒粒子利用病毒包膜糖蛋白结合并侵入宿主细胞。在细胞质中,病毒RNA基因组作为mRNA,并产生作为长多蛋白的病毒蛋白,该多蛋白由宿主和病毒蛋白酶切割。子代病毒粒子通过出芽组装进入内质网/高尔基体,糖蛋白在那里成熟,并在细胞表面释放。从病毒附着到子代释放的复制周期的所有阶段都应该是抗病毒靶点。我们从自然资源中寻找抗病毒候选物已有大约20年了。到目前为止,我们已经发现了几类具有独特抗病毒作用的化合物。其中,阴离子物质干扰病毒附着和/或进入,几种物质抑制病毒特异性糖蛋白的成熟,小分子可以抑制病毒从感染细胞中释放,甘油衍生物降低病毒的致病性,一些化合物发挥杀病毒作用,损害病毒感染宿主细胞的能力。通过在培养细胞系中使用HCV复制系统,这些物质可能值得作为新型抗HCV药物进行评估。