Backbone Modified Peptide-nucleic Acids as Antiviral Agents Against Hepatitis C

主链修饰肽核酸作为丙型肝炎抗病毒剂

• 批准号: 8253898
• 负责人: MIHAELA R MIHAILESCU
• 金额: $ 6.2万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2013-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8253898
• 关键词: 3' Untranslated Regions; 5' Untranslated Regions; Affective; Affinity; Antiviral Agents; Base Pairing; Binding; Biological; Cells; Child; Circular Dichroism Spectroscopy; Code; Collaborations; Combined Modality Therapy; Complementary DNA; Complementary RNA; Complex; Conserved Sequence; Core Protein; DNA; Data; Development; Family; Flaviviridae; Future; Genetic; Genetic Transcription; Genome; Genomics; Genotype; Glycine; Glycoproteins; Goals; Health; Hepatitis C; Hepatitis C virus; Incidence; Laboratories; Life Cycle Stages; Lipids; Liver Cirrhosis; Methods; Modification; Molecular; NMR Spectroscopy; North Carolina; Nucleic Acids; Nucleocapsid; Open Reading Frames; Patients; Peptide Hydrolases; Peptide Nucleic Acids; Pharmaceutical Preparations; Play; Primary carcinoma of the liver cells; RNA; RNA-Directed RNA Polymerase; Recombinant Interferon Alfa; Research; Research Personnel; Ribavirin; Role; Series; Specificity; Sugar Phosphates; Testing; Therapeutic; Training; Translations; Universities; Vertebral column; Viral; Viral Proteins; Virion; Virus; Virus Replication; analog; biophysical chemistry; career; design; gel electrophoresis; in vivo; inhibitor/antagonist; member; middle age; novel therapeutics; nuclease; nucleic acid inhibitor; viral RNA; young woman

DESCRIPTION (provided by applicant): With more than 200 million people infected, the Hepatitis C virus (HCV) poses a major health problem worldwide. The current therapy to treat HCV infections, which uses recombinant alpha interferon and ribavirin, is efficient only in less than 50% of the patients and chronically HCV infected patients can develop serious health problems which include liver cirrhosis and hepatocellular carcinoma. Thus, there is an urgent need for the development of new therapeutic strategies. HCV has its genome encoded by a positive-strand RNA, which contains an open reading frame flanked by 5'- and 3'-untranslated regions (UTRs). Despite the high mutational rate of the virus, the HCV RNA coding region, as well as its 5'- and 3'-UTRs contain evolutionary conserved sequences proposed to be involved in an intricate array of long-range interactions with each other. Although the molecular mechanisms of these interactions are not all clear, genetic data indicates that they play vital roles in the virus replication and translation. Thus, the inhibition of these interactions which involve regions of 100% conservancy among all HCV genotypes, is an attractive antiviral strategy, given their essential roles in the HCV life cycle, and this is the long term goal of this project, which has the following specific aims: Specific aim 1. Design and synthesis of peptide-nucleic acids which target conserved regions of the HCV genomic RNA essential for the viral replication and translation. Specific aim 2. Analyze the ability of the designed PNAs to disrupt the long-range interactions between regions of highly conservancy within the HCV RNA genome, inhibiting HCV replication and translation. PUBLIC HEALTH RELEVANCE: The significance of the proposed research is evident, as the peptide nucleic acid (PNA) inhibitors proposed to be synthesized and analyzed in these studies, target regions of 100% conservancy within the HCV genome. These ?-modified PNAs aim to disrupt essential long- range interactions between these regions, interactions whose biological significance for the viral life cycle has been established by genetic data. Thus, these studies have the potential to identify efficient inhibitors for HCV replication and translation, an imperatve task, considering the major health problem posed worldwide by the HCV infection, whose incidence is over 200 million people.

描述（由申请人提供）：随着超过2亿人感染，丙型肝炎病毒（HCV）在全球范围内构成了一个主要的健康问题。目前使用重组α干扰素和利巴韦林治疗HCV感染的疗法仅在少于50%的患者中有效，并且慢性HCV感染的患者可发展严重的健康问题，包括肝硬化和肝细胞癌。因此，迫切需要开发新的治疗策略。HCV的基因组由正链RNA编码，其包含侧接5 '和3'非翻译区（UTR）的开放阅读框。尽管病毒的突变率很高，但HCV RNA编码区及其5 '-和3'-UTR含有进化上保守的序列，这些序列被认为参与了一系列复杂的相互作用。虽然这些相互作用的分子机制还不完全清楚，但遗传数据表明它们在病毒复制和翻译中起着重要作用。因此，考虑到它们在HCV生命周期中的重要作用，抑制这些涉及所有HCV基因型中100%保守区域的相互作用是一种有吸引力的抗病毒策略，并且这是本发明的长期目标。 该项目有以下具体目标：具体目标1。针对病毒复制和翻译所必需的HCV基因组RNA保守区域的肽-核酸的设计和合成。具体目标2。分析设计的PNA破坏HCV RNA基因组内高度保守区域之间的长程相互作用，抑制HCV复制和翻译的能力。 公共卫生关系：所提出的研究的意义是显而易见的，因为肽核酸（PNA）抑制剂建议在这些研究中合成和分析，HCV基因组内100%保护的目标区域。这些？修饰的PNA旨在破坏这些区域之间基本的长程相互作用，这种相互作用对于病毒生命周期的生物学意义已经由遗传数据确定。因此，这些研究有可能确定HCV复制和翻译的有效抑制剂，考虑到HCV感染在世界范围内造成的主要健康问题，其发病率超过2亿人，这是一项迫切的任务。