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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：
8035922
负责人：
Thomas C Hermann
金额：
$ 35.39万
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/8035922
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 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 Peptides Permeability Pharmaceutical Preparations 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 combat design drug development functional group improved inhibitor/antagonist novel novel therapeutics patient population 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）：拟议的项目旨在发现针对丙型肝炎病毒（HCV）基因组功能RNA成分的抗病毒化合物。该项目的具体目标是：1)确定HCV基因组中可用于生化和生物物理表征的功能性RNA元件的子域；2)通过RNA-motif分析评估子结构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，确定RNA亚结构域的优先级以供进一步研究；4)开发用于生化和生物物理表征以及RNA亚域结晶的寡核苷酸模型系统；5)开发HCV亚域的RNA亲和力测定；6)通过x射线晶体学确定RNA亚域的三维结构；7)设计和合成基于两类RNA“友好”化合物的新型RNA偏向配体；8)通过亲和力测定鉴定与选定HCV RNA亚结构域结合的配体；9)检测阳性结合物的靶特异性；10)通过开发和应用HCV ires驱动的体外翻译试验来检测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通透性；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)通过晶体学确定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结合亲和力的修饰配体。由于缺乏疫苗和直接抗病毒药物来治疗或预防丙型肝炎病毒的传播，迫切需要开发新的治疗方法。对于识别HCV基因组结构功能域并干扰蛋白质合成的小分子来说，病毒RNA是一个有吸引力的靶标。合理的结构指导设计以及RNA“友好”化合物的合成化学将促进RNA结合分子的产生，这些分子对HCV蛋白合成具有特异性靶标识别和生物活性。这项研究的目的是发现新的分子类别，这将大大促进抗HCV感染的强效抗病毒药物的开发。这些进展对人类未来战胜病毒性疾病的能力至关重要。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hepatitis C virus translation inhibitors targeting the internal ribosomal entry site.

针对内部核糖体入口部位的丙型肝炎病毒翻译抑制剂。

DOI：
10.1021/jm401312n
发表时间：
2014-03-13
期刊：
Journal of medicinal chemistry
影响因子：
7.3
作者：
Dibrov SM;Parsons J;Carnevali M;Zhou S;Rynearson KD;Ding K;Garcia Sega E;Brunn ND;Boerneke MA;Castaldi MP;Hermann T
通讯作者：
Hermann T

Nanopore-based conformational analysis of a viral RNA drug target.