Core as a novel viral target for hepatitis C drugs.
Core as a novel viral target for hepatitis C drugs.
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DOI：
10.3390/v2081734
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发表时间：
2010-08
期刊：
影响因子：
--
通讯作者：
Mousseau G
中科院分区：
文献类型：
--
作者：
Strosberg AD;Kota S;Takahashi V;Snyder JK;Mousseau G
丙型肝炎病毒（HCV）感染全球超过1.3亿人，是肝脏疾病的主要原因。没有疫苗可用。由于聚乙二醇干扰素联合利巴韦林的标准治疗耐受性差，治愈率不到一半，因此迫切需要新型HCV特异性药物。目前在临床上已经描述了10种潜在的HCV靶蛋白中的3种：NS 3/NS 4A蛋白酶，NS 5 B聚合酶和NS 5A，一种调节磷蛋白。我们在这里提出的核心，病毒衣壳蛋白，作为另一个有吸引力的，非酶的目标，针对这一类新的抗HCV药物可以提高。核心在病毒体的形成中起主要作用，并与几种细胞蛋白相互作用，其中一些蛋白参与宿主对病毒的防御机制。这是所有HCV蛋白中最保守的，需要寡聚化以作为病毒颗粒组装的组织者。使用核心二聚化作为能量转移筛选测定的基础，鉴定了不仅抑制核心-核心相互作用，而且阻断细胞培养物中病毒产生的肽和小分子。最初的化学优化导致化合物在个位数微摩尔浓度下具有活性。核心抑制剂可以与其他HCV药物联合使用，以提供丙型肝炎的新治疗方法。
Hepatitis C virus (HCV) infects over 130 million people worldwide and is a major cause of liver disease. No vaccine is available. Novel specific drugs for HCV are urgently required, since the standard-of-care treatment of pegylated interferon combined with ribavirin is poorly tolerated and cures less than half of the treated patients. Promising, effective direct-acting drugs currently in the clinic have been described for three of the ten potential HCV target proteins: NS3/NS4A protease, NS5B polymerase and NS5A, a regulatory phosphoprotein. We here present core, the viral capsid protein, as another attractive, non-enzymatic target, against which a new class of anti-HCV drugs can be raised. Core plays a major role in the virion’s formation, and interacts with several cellular proteins, some of which are involved in host defense mechanisms against the virus. This most conserved of all HCV proteins requires oligomerization to function as the organizer of viral particle assembly. Using core dimerization as the basis of transfer-of-energy screening assays, peptides and small molecules were identified which not only inhibit core-core interaction, but also block viral production in cell culture. Initial chemical optimization resulted in compounds active in single digit micromolar concentrations. Core inhibitors could be used in combination with other HCV drugs in order to provide novel treatments of Hepatitis C.
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