Developing antiviral agents that inhibit HCV translation

描述（由申请人提供）：据估计，全球有超过1.7亿人感染丙型肝炎病毒（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介导的针对HCV感染的翻译起始。通过在PTC建立的HCV IRES翻译实验，我们发现了低分子量先导化合物，它们对HCV IRES介导的翻译具有选择性。本申请的目的是对这些化合物的活性、选择性、细胞毒性和药理学特性进行优化。拟议研究的一个成功结果将是确定一种开发候选药物，该候选药物作用于HCV ires促进的翻译起始。

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.