Developing antiviral agents that inhibit HCV translation

描述（由申请人提供）：据估计，全世界有超过1.7亿人感染丙型肝炎病毒（HCV）。目前，有有限的治疗剂和没有疫苗可用于HCV感染。因此，有必要开发新的抗HCV药物。HCV是黄病毒科（Flaviviridae）的成员。HCV基因组包含编码病毒蛋白的长的、单个开放阅读框mRNA。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，它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以及与细胞起始因子的独特相互作用模式。基于我们在药物发现方面的专业知识，即靶向转录后控制，我们正在研究HCV IRES介导的抗HCV感染的翻译起始。使用PTC建立的HCV IRES翻译测定，我们已经鉴定了对HCV IRES介导的翻译具有选择性的低分子量先导化合物。该应用程序的目标是进行铅优化，以提高这些化合物的活性，选择性，细胞毒性和药理学特性。拟议研究的成功结果将是确定对HCV IRES促进的翻译起始起作用的开发候选物。

DESCRIPTION (provided by applicant): It is estimated that over 170 million people are infected by hepatitis C virus (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. 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 our expertise in drug discovery, i.e. targeting Post-Transcription-Control, we are pursuing HCV IRES-mediated translation initiation against HCV infection. Using HCV IRES translation assays established at PTC, we have identified low molecular weight lead compounds that are selective against HCV IRES-mediated translation. The goal of the application is to perform lead optimization for improving the activity, selectivity, cytotoxicity and pharmacological properties of these compounds. A successful outcome of the proposed studies will be the identification of a development candidate(s) that acts on HCV IRES-facilitated translation initiation.