New Antiviral Therapies for Hepatitis C Infection

丙型肝炎感染的新抗病毒疗法

基本信息

批准号：
7268292
负责人：
Thomas C Hermann
金额：
$ 37.16万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-15 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7268292
关键词：
2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole Adopted Advanced Development Affinity Alcohols Amines Antibiotics Antiviral Agents Antiviral Therapy Binding Binding Sites Biochemical Biological Biological Assay Biological Factors Biological Models Calorimetry Chemicals Class Code Complex Crystallization Crystallography Data Development Elements Fluorescence Future Gel Generations Genetic Genome Genotype Goals Hepatitis C Hepatitis C virus Humanities In Vitro Indium Infection Internal Ribosome Entry Site Investigation Lead Ligand Binding Ligands Mammalian Cell Modeling Nature Oligonucleotides Patients Peptides Permeability Pharmaceutical Preparations Population Protein Biosynthesis Publishing RNA Research Research Personnel Ribosomes Specificity Staging Structure Synthesis Chemistry Testing Therapeutic Titrations Translations Vaccines Viral Viral Proteins Virus Virus Diseases Work X-Ray Crystallography base concept design drug development functional group improved inhibitor/antagonist novel novel therapeutics prevent programs small molecule stem three dimensional structure translation assay

项目摘要

DESCRIPTION (provided by applicant): The proposed program intends to discover antiviral compounds that target functional RNA components of the hepatitis C virus (HCV) genome. The specific aims of this project are to: 1) define subdomains of functional RNA elements in the HCV genome that are amenable to biochemical and biophysical characterization; 2) assess subdomains by RNA-motif analysis for the potential to contain ligand-binding sites; 3) prioritize RNA subdomains for further investigation by assessment of potential ligand binding sites and published biological data; 4) develop oligonucleotide model systems for biochemical and biophysical characterization as well as crystallization of RNA subdomains; 5) develop RNA affinity assays for the HCV subdomains; 6) determine the three-dimensional structure of RNA subdomains by X-ray crystallography; 7) design and synthesize novel RNA-biased ligands based on two chemical classes of RNA-"friendly" compounds; 8) identify ligands that bind to selected HCV RNA subdomains by using affinity assays; 9) test the positive binders for their target specificity; 10) test ligands for their interference with viral translation by developing and applying an HCV IRES-driven in vitro translation assay; 11) test translation inhibitors for permeability in mammalian cells; 12) test translation inhibitors for inhibition of viral replication in mammalian cells; 13) determine the three-dimensional structure of RNA-ligand complexes by crystallography; 14) design modified ligands with potentially improved binding affinity by using structural information. The lack of a vaccine and direct antiviral drugs to treat or prevent the spread of HCV creates an urgent need for the development of new therapeutics. The viral RNA is an attractive target for small molecules that recognize structured functional domains of the HCV genome and interfere with protein synthesis. Rational structure-guided design along with synthetic chemistry of RNA-"friendly" compounds will facilitate the generation of RNA-binding molecules that display specific target recognition and biological activity against HCV protein synthesis. This research is aimed at the discovery of new classes of molecules that will significantly advance the development of potent antiviral drugs for combating HCV infection. Such advances are critical for the future ability of humanity to defeat viral diseases.

描述（由申请人提供）：拟议的计划旨在发现针对丙型肝炎病毒（HCV）基因组功能性RNA成分的抗病毒化合物。该项目的具体目标是： 1) 定义 HCV 基因组中功能性 RNA 元件的子域，这些子域适合生化和生物物理表征； 2) 通过RNA基序分析评估子域是否含有配体结合位点； 3) 通过评估潜在的配体结合位点和已发表的生物学数据，优先考虑 RNA 子域以进行进一步研究； 4) 开发用于生化和生物物理表征以及RNA子结构域结晶的寡核苷酸模型系统； 5) 开发 HCV 子域的 RNA 亲和力测定； 6)通过X射线晶体学确定RNA亚结构域的三维结构； 7) 基于两种化学类别的RNA“友好”化合物，设计和合成新型RNA偏向配体； 8) 通过亲和力测定鉴定与选定的 HCV RNA 亚结构域结合的配体； 9) 测试阳性结合剂的目标特异性； 10) 通过开发和应用 HCV IRES 驱动的体外翻译测定来测试配体对病毒翻译的干扰； 11)测试翻译抑制剂在哺乳动物细胞中的渗透性； 12)测试翻译抑制剂对哺乳动物细胞中病毒复制的抑制作用； 13)通过晶体学测定RNA-配体复合物的三维结构； 14) 利用结构信息设计具有潜在改善的结合亲和力的修饰配体。由于缺乏治疗或预防 HCV 传播的疫苗和直接抗病毒药物，迫切需要开发新疗法。病毒 RNA 是识别 HCV 基因组结构功能域并干扰蛋白质合成的小分子的有吸引力的靶标。合理的结构引导设计以及RNA“友好”化合物的合成化学将促进RNA结合分子的产生，这些分子表现出针对HCV蛋白质合成的特异性靶标识别和生物活性。这项研究旨在发现新型分子，这些分子将显着促进有效抗病毒药物的开发，以对抗丙型肝炎病毒感染。这些进步对于人类未来战胜病毒性疾病的能力至关重要。