A Novel Inhibitor of Dengue Virus Replication That Targets the Capsid Protein
A Novel Inhibitor of Dengue Virus Replication That Targets the Capsid Protein
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DOI：
10.1128/aac.01429-12
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发表时间：
2013-01-01
影响因子：
4.9
通讯作者：
Jordan, Robert
中科院分区：
文献类型：
--
作者：
Byrd, Chelsea M.;Dai, Dongcheng;Jordan, Robert
登革病毒（DENV）每年感染全球5000万至1亿人，其中50万人发展成严重危及生命的疾病。这种由蚊子传播的疾病在大多数热带和亚热带国家流行，在过去十年中传播迅速。虽然在临床试验中有几种有希望的候选疫苗，但目前还没有批准的疫苗或治疗剂可用于治疗登革热感染。在这里，我们描述了一种新的小分子化合物ST-148，它是体外所有四种DENV血清型的有效抑制剂。ST-148显著降低了重要器官中的病毒血症和病毒载量，并倾向于降低AG129小鼠中DENV感染的非致死模型中血浆中的细胞因子水平。化合物抗性映射到DENV衣壳（C）基因，并且ST-148与C蛋白的直接相互作用通过在化合物存在下蛋白质的固有荧光的改变来表明。因此，ST-148似乎与DENV C蛋白相互作用并抑制病毒复制周期的不同步骤。
Dengue viruses (DENV) infect 50 to 100 million people worldwide per year, of which 500,000 develop severe life-threatening disease. This mosquito-borne illness is endemic in most tropical and subtropical countries and has spread significantly over the last decade. While there are several promising vaccine candidates in clinical trials, there are currently no approved vaccines or therapeutics available for treatment of dengue infection. Here, we describe a novel small-molecule compound, ST-148, that is a potent inhibitor of all four serotypes of DENV in vitro. ST-148 significantly reduced viremia and viral load in vital organs and tended to lower cytokine levels in the plasma in a nonlethal model of DENV infection in AG129 mice. Compound resistance mapped to the DENV capsid (C) gene, and a direct interaction of ST-148 with C protein is suggested by alterations of the intrinsic fluorescence of the protein in the presence of compound. Thus, ST-148 appears to interact with the DENV C protein and inhibits a distinct step(s) of the viral replication cycle.