Isolation of Genetic Suppressor Elements Against Hepatitis C Virus

抗丙型肝炎病毒基因抑制元件的分离

基本信息

  • 批准号:
    7708619
  • 负责人:
  • 金额:
    $ 22.48万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-08-01 至 2011-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infection is a major public health problem, putting infected individuals (~180 million worldwide) at risk of developing cirrhosis, hepatocellular carcinoma, and liver failure. Chronic hepatitis C is the leading cause for liver transplantation. Current standard interferon-based therapy, a costly and time-consuming process, has only a ~50% cure rate, and no anti-HCV drugs have yet been approved for hepatitis C therapy. Despite the promise shown by HCV-specific proteases and polymerases as drug targets, the rapid emergence of viral resistance indicates that additional targets and combinations of antivirals will be necessary for effective treatment. We propose to isolate genetic suppressor elements (GSEs) from a library comprising a fragmented HCV genome which could be used both as potent anti-HCV therapeutic agents and as probes to identify and validate new targets for further drug screening. GSEs are nucleic acid or protein/peptide molecules derived from a gene or genome that act as transdominant inhibitors of a particular biological function through a variety of mechanisms, which includes binding to and blocking essential interaction surfaces for protein activity. In order to identify GSEs from within the HCV genome that exert inhibitory activity against HCV, a novel function-based selection system will be developed and implemented. Briefly, a fragmented HCV genome will be delivered to a hepatoma derivative cell line that is sensitive to a cytopathic effect exerted by HCV. The cells containing the HCV-derived genetic fragments will be subjected to a cytopathic challenge by exogenously administered cell culture-derived HCV (HCVcc) infectious particles, and cells surviving this HCV challenge will be enriched in GSEs that exert an inhibitory effect against HCV. Iterative application of this selection procedure will result in the identification of highly potent GSEs that protect cells against HCV infection and cytotoxicity. Preliminary studies will evaluate the degree of the protective effect conferred by the identified GSEs against HCV-mediated cytotoxicity, and the stage in the HCV life cycle at which the anti-HCV effect of the GSEs is exerted. Future studies originating from the identified GSEs are expected to reveal the molecular basis of the anti-HCV GSE activity, thus providing new leads for anti-HCV drug development. It is expected that the GSEs identified from the proposed research, and molecular mimetics derived therefrom, will inhibit HCV infection/propagation through diverse mechanisms, including the inhibition of virus-host cell interactions, thus contributing to the urgent quest for new and effective HCV antivirals on multiple fronts. PUBLIC HEALTH RELEVANCE: Infection by hepatitis C virus is a serious global health problem that causes numerous debilitating liver conditions. The current treatment regime for hepatitis C is time-consuming, expensive, and often ineffective, creating an urgent need for new and effective drugs. Novel anti-hepatitis C genetic suppressor elements isolated from this research will serve both as hepatitis C drugs, and as keys to open doors to new avenues of research in hepatitis C antiviral development.
描述(申请人提供):丙型肝炎病毒(丙型肝炎病毒)感染是一个主要的公共卫生问题,使感染者(全球约1.8亿人)面临发展为肝硬变、肝细胞癌和肝功能衰竭的风险。慢性丙型肝炎是肝移植的主要原因。目前基于干扰素的标准治疗是一个昂贵和耗时的过程,治愈率只有50%左右,而且还没有抗丙型肝炎药物被批准用于丙型肝炎的治疗。尽管丙型肝炎病毒特异的蛋白酶和聚合酶有望成为药物靶点,但病毒耐药性的迅速出现表明,有效的治疗需要更多的靶点和抗病毒药物的组合。我们建议从包含一个片段的丙型肝炎病毒基因组的文库中分离出遗传抑制元件(GSE),该文库既可以作为有效的抗丙型肝炎病毒治疗药物,也可以作为探针来识别和验证进一步药物筛选的新靶点。GSE是来源于基因或基因组的核酸或蛋白质/多肽分子,通过各种机制作为特定生物功能的跨显性抑制物,包括结合和阻断蛋白质活性的基本相互作用面。为了从丙型肝炎病毒基因组中识别对丙型肝炎病毒具有抑制活性的GSE,将开发和实现一种新的基于功能的选择系统。简而言之,一个片段的丙型肝炎病毒基因组将被传递给一个对丙型肝炎病毒所产生的细胞病变效应敏感的肝癌衍生细胞系。含有丙型肝炎病毒基因片段的细胞将受到外源性细胞培养衍生丙型肝炎病毒(HCVcc)感染颗粒的细胞病变攻击,而在这种丙型肝炎病毒挑战中存活的细胞将富含对丙型肝炎病毒起抑制作用的GSE。反复应用这一选择程序将导致高度有效的GSE的鉴定,以保护细胞免受丙型肝炎病毒感染和细胞毒性。初步研究将评估已鉴定的GSE对丙型肝炎病毒介导的细胞毒性的保护作用程度,以及在丙型肝炎病毒生命周期中发挥抗丙型肝炎病毒作用的阶段。来自已鉴定的GSE的未来研究有望揭示抗丙型肝炎病毒GSE活性的分子基础,从而为抗丙型肝炎药物的开发提供新的线索。预计从拟议的研究中确定的GSE及其衍生的分子模拟物将通过不同的机制(包括抑制病毒与宿主细胞的相互作用)抑制丙型肝炎病毒的感染/繁殖,从而在多个方面促进对新的有效的丙型肝炎病毒抗病毒药物的迫切探索。公共卫生相关性:丙型肝炎病毒感染是一个严重的全球健康问题,会导致许多肝脏虚弱。目前丙型肝炎的治疗方案耗时、昂贵,而且往往无效,因此迫切需要新的有效药物。从这项研究中分离出的新型抗丙型肝炎基因抑制因子将既用作丙型肝炎药物,也将成为打开丙型肝炎抗病毒开发研究新途径的钥匙。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Zhilei Chen其他文献

Zhilei Chen的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Zhilei Chen', 18)}}的其他基金

Oral Protein Therapeutics Against C. difficile Associated Colitis
针对艰难梭菌相关结肠炎的口服蛋白质疗法
  • 批准号:
    10455793
  • 财政年份:
    2021
  • 资助金额:
    $ 22.48万
  • 项目类别:
A Novel Technology for Engineering Binders to Membrane Proteins
膜蛋白结合剂工程新技术
  • 批准号:
    10040547
  • 财政年份:
    2020
  • 资助金额:
    $ 22.48万
  • 项目类别:
A Novel Technology for Engineering Binders to Membrane Proteins
膜蛋白结合剂工程新技术
  • 批准号:
    10227122
  • 财政年份:
    2020
  • 资助金额:
    $ 22.48万
  • 项目类别:
Internal Toxin Neutralizer for Treating STEC-infection
用于治疗 STEC 感染的内毒素中和剂
  • 批准号:
    9886184
  • 财政年份:
    2019
  • 资助金额:
    $ 22.48万
  • 项目类别:
Artificial Ecology Sink as prophylaxis against viral infection
人工生态水槽预防病毒感染
  • 批准号:
    9348755
  • 财政年份:
    2017
  • 资助金额:
    $ 22.48万
  • 项目类别:
Broadly neutralizing non-antibody protein for treating clostridium difficile infection
用于治疗艰难梭菌感染的广泛中和非抗体蛋白
  • 批准号:
    9293991
  • 财政年份:
    2016
  • 资助金额:
    $ 22.48万
  • 项目类别:
Broadly neutralizing non-antibody protein for treating clostridium difficile infection
用于治疗艰难梭菌感染的广泛中和非抗体蛋白
  • 批准号:
    9167525
  • 财政年份:
    2016
  • 资助金额:
    $ 22.48万
  • 项目类别:
Isolation of Genetic Suppressor Elements Against Hepatitis C Virus
抗丙型肝炎病毒基因抑制元件的分离
  • 批准号:
    7905080
  • 财政年份:
    2009
  • 资助金额:
    $ 22.48万
  • 项目类别:

相似海外基金

Development of a new generation of antiviral agents that are effective against drug-resistant viruses and prevent serious illness and sequelae.
开发新一代抗病毒药物,可有效对抗耐药病毒并预防严重疾病和后遗症。
  • 批准号:
    23K18186
  • 财政年份:
    2023
  • 资助金额:
    $ 22.48万
  • 项目类别:
    Grant-in-Aid for Challenging Research (Exploratory)
A versatile structure-based therapeutic platform for development of VHH-based antitoxin and antiviral agents
一个多功能的基于结构的治疗平台,用于开发基于 VHH 的抗毒素和抗病毒药物
  • 批准号:
    10560883
  • 财政年份:
    2023
  • 资助金额:
    $ 22.48万
  • 项目类别:
Genetically encoded bicyclic peptide libraries for the discoveryof novel antiviral agents
用于发现新型抗病毒药物的基因编码双环肽库
  • 批准号:
    10730692
  • 财政年份:
    2021
  • 资助金额:
    $ 22.48万
  • 项目类别:
Design and synthesis of nucleosides to develop antiviral agents and oligonucleotide therapeutics
设计和合成核苷以开发抗病毒药物和寡核苷酸疗法
  • 批准号:
    21K06459
  • 财政年份:
    2021
  • 资助金额:
    $ 22.48万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Genetically encoded bicyclic peptide libraries for the discoveryof novel antiviral agents
用于发现新型抗病毒药物的基因编码双环肽库
  • 批准号:
    10189880
  • 财政年份:
    2021
  • 资助金额:
    $ 22.48万
  • 项目类别:
Computer-aided identification and synthesis of novel broad-spectrum antiviral agents
新型广谱抗病毒药物的计算机辅助鉴定和合成
  • 批准号:
    2404261
  • 财政年份:
    2020
  • 资助金额:
    $ 22.48万
  • 项目类别:
    Studentship
Develop broad-spectrum antiviral agents against COVID-19 based on innate immune response to SARS-CoV-2 infection
基于对 SARS-CoV-2 感染的先天免疫反应,开发针对 COVID-19 的广谱抗病毒药物
  • 批准号:
    10222540
  • 财政年份:
    2020
  • 资助金额:
    $ 22.48万
  • 项目类别:
Develop broad-spectrum antiviral agents against COVID-19 based on innate immune response to SARS-CoV-2 infection
基于对 SARS-CoV-2 感染的先天免疫反应,开发针对 COVID-19 的广谱抗病毒药物
  • 批准号:
    10669717
  • 财政年份:
    2020
  • 资助金额:
    $ 22.48万
  • 项目类别:
Association between sedentary lifestyle and liver cancer development in hepatitis C patients treated with direct-acting antiviral agents
接受直接抗病毒药物治疗的丙型肝炎患者久坐的生活方式与肝癌发展之间的关系
  • 批准号:
    20K10713
  • 财政年份:
    2020
  • 资助金额:
    $ 22.48万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Develop broad-spectrum antiviral agents against COVID-19 based on innate immune response to SARS-CoV-2 infection
基于对 SARS-CoV-2 感染的先天免疫反应,开发针对 COVID-19 的广谱抗病毒药物
  • 批准号:
    10174522
  • 财政年份:
    2020
  • 资助金额:
    $ 22.48万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了