Developing antiviral agents that inhibit HCV translation

描述（由申请人提供）：据估计，全球有超过1.7亿人感染HCV。目前，治疗丙肝病毒感染的药物有限，也没有疫苗可用。因此，有必要开发新的抗hcv药物。丙型肝炎病毒是黄病毒科的一员。HCV基因组包含一个长而单一的开放阅读框mRNA，用于编码病毒蛋白。在HCV RNA的5'非翻译区发现了一个内部核糖体进入位点（IRES）顺式作用元件，该元件指导病毒蛋白的翻译起始。HCV IRES具有保守的一级序列，独特的二级和三级结构，与细胞起始因子具有独特的相互作用模式。基于申请人在药物发现方面的专业知识，即靶向转录后控制，研究人员正在研究HCV ires介导的针对HCV感染的翻译起始。使用PTC Therapeutics， Inc建立的HCV IRES翻译测定，申请人已经确定了对HCV IRES介导的翻译有活性的低分子量化合物。该研究的目标是进一步评估化合物对帽依赖翻译的选择性，HCV IRES命中的细胞毒性特征及其在自我复制的亚基因组HCV系统中的功效。拟议研究的一个成功结果将是确定对HCV ires促进的翻译起始起作用的主要候选药物。

DESCRIPTION (provided by applicant): It is estimated that over 170 million people are infected by HCV worldwide. Currently, there are limited therapeutic agents and no vaccine available for HCV infection. Thus, it is necessary to develop new anti-HCV drugs. The HCV is a member of the family Flaviviridae. The HCV genome contains a long, single open reading frame mRNA that encodes the viral proteins. An internal ribosome entry site (IRES)cis-acting element was identified in the 5' untranslated region of the HCV RNA, which directs translation initiation of the viral proteins. The HCV IRES has conserved primary sequences, unique secondary and tertiary structures, and a distinct interaction mode with cellular initiation factors. Based on the applicant's expertise in drug discovery, i.e. targeting post-transcriptional control, the investigators are pursuing HCV IRES-mediated translation initiation against HCV infection. Using HCV IRES translation assays established at PTC Therapeutics, Inc., the applicants have identified low molecular weight compounds that are active against HCV IRES-mediated translation. The goal of the proposed research is to further assess compound selectivity to cap-dependent translation, the cytotoxicity profiles of the HCV IRES hits and their efficacy in a self-replicating subgenomic HCV system. A successful outcome of the proposed studies will be the identification of lead candidates that act on HCV IRES-facilitated translation initiation.