New Antiviral Therapies for Hepatitis C Infection

丙型肝炎感染的新抗病毒疗法

• 批准号: 7395036
• 负责人: Thomas C Hermann
• 金额: $ 36.71万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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/7395036
• 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

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）：拟议的计划打算发现靶向丙型肝炎病毒（HCV）基因组的功能性RNA成分的抗病毒化合物。该项目的具体目的是：1）定义HCV基因组中功能性RNA元素的子域，这些元素可与生化和生物物理特征相提并论； 2）通过RNA-MOTIF分析评估子域，以含有配体结合位点的潜力； 3）优先考虑RNA子域，以评估潜在的配体结合位点并发表的生物学数据，以进一步研究； 4）开发用于生化和生物物理表征以及RNA亚域的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子域的三维结构； 7）设计和合成新型的RNA偏置配体，基于两种化学类RNA“友好”化合物； 8）通过使用亲和力测定法确定与选定的HCV RNA子域结合的配体； 9）测试其目标特异性的阳性粘合剂； 10）测试配体通过开发和应用HCV IRES驱动的体外翻译测定法对病毒翻译的干扰； 11）测试翻译抑制剂在哺乳动物细胞中的渗透性； 12）测试翻译抑制剂抑制哺乳动物细胞中病毒复制的抑制剂； 13）通过晶体学确定RNA-配体复合物的三维结构； 14）使用结构信息设计具有潜在改善结合亲和力的修饰配体。缺乏治疗或防止HCV传播的疫苗和直接抗病毒药物迫切需要开发新的治疗剂。病毒RNA是识别HCV基因组结构化功能结构域并干扰蛋白质合成的小分子的有吸引力的靶标。理性结构引导的设计以及RNA“友好”化合物的合成化学将有助于生成RNA结合分子，这些分子显示出特定的靶识别和针对HCV蛋白合成的生物学活性。这项研究旨在发现新的分子，这些分子将大大推动有效的抗病毒药物来打击HCV感染。这种进步对于人类未来击败病毒疾病的能力至关重要。