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:
- 金额:$ 35.39万
- 依托单位:
- 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:
- 关键词:2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazoleAdoptedAdvanced DevelopmentAffinityAlcoholsAminesAntibioticsAntiviral AgentsAntiviral TherapyBindingBinding SitesBiochemicalBiologicalBiological AssayBiological FactorsBiological ModelsCalorimetryChemicalsCodeComplexCrystallizationCrystallographyDataDevelopmentElementsFluorescenceFutureGelGenerationsGeneticGenomeGenotypeGoalsHepatitis CHepatitis C virusHumanitiesIn VitroIndiumInfectionInternal Ribosome Entry SiteInvestigationLeadLigand BindingLigandsMammalian CellModelingNatureOligonucleotidesPeptidesPermeabilityPharmaceutical PreparationsProtein BiosynthesisPublishingRNAResearchResearch PersonnelRibosomesSpecificityStagingStructureSynthesis ChemistryTestingTherapeuticTitrationsTranslationsVaccinesViralViral ProteinsVirusVirus DiseasesWorkX-Ray Crystallographybasecombatdesigndrug developmentfunctional groupimprovedinhibitor/antagonistnovelnovel therapeuticspatient populationpreventprogramssmall moleculestemthree dimensional structuretranslation 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(丙型肝炎病毒)基因组的功能性RNA成分的抗病毒化合物。该项目的具体目标是:1)确定丙型肝炎病毒基因组中适合生化和生物物理特性的功能RNA元件的亚区;2)通过RNA基序分析评估含有配基结合位点的可能性;3)通过评估潜在的配基结合位点和公开的生物学数据优先进行RNA亚域的进一步研究;4)建立用于生化和生物物理特性以及RNA亚区结晶的寡核苷酸模型系统;5)建立用于丙型肝炎病毒亚区的RNA亲和分析;6)通过X射线结晶学确定RNA亚区的三维结构;7)设计和合成基于两类RNA“友好”化合物的新型RNA导向配体;8)通过亲和力分析确定与选定的丙型肝炎病毒RNA亚域结合的配体;9)测试阳性结合子的靶特异性;10)通过开发和应用丙型肝炎病毒IRES驱动的体外翻译试验,测试其对病毒翻译的干扰;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病毒在哺乳动物细胞中的复制;13)通过结晶学确定RNA-配体复合体的三维结构;14)利用结构信息设计具有潜在提高结合亲和力的修饰配体。由于缺乏疫苗和直接的抗病毒药物来治疗或防止丙型肝炎病毒的传播,迫切需要开发新的治疗方法。病毒RNA是识别丙型肝炎病毒基因组结构功能区并干扰蛋白质合成的小分子的一个有吸引力的靶标。合理的结构指导设计和RNA友好化合物的合成化学将促进RNA结合分子的产生,这些分子显示出针对丙型肝炎病毒蛋白合成的特定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,这些分子将显著推动有效的抗病毒药物的开发,以对抗丙型肝炎病毒感染。这些进展对人类未来战胜病毒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:
- 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.
- DOI:10.1021/nn501969r
- 发表时间:2014-06-24
- 期刊:
- 影响因子:17.1
- 作者:Shasha C;Henley RY;Stoloff DH;Rynearson KD;Hermann T;Wanunu M
- 通讯作者:Wanunu M
Synthesis and crystal structure of a phenazine N-oxide.
N-氧化物吩嗪的合成和晶体结构。
- DOI:10.1007/s10870-013-0456-4
- 发表时间:2013
- 期刊:
- 影响因子:0.8
- 作者:Ding,Kejia;Dibrov,SergeyM;Hermann,Thomas
- 通讯作者:Hermann,Thomas
Conformational flexibility of viral RNA switches studied by FRET.
- DOI:10.1016/j.ymeth.2015.09.013
- 发表时间:2015-12
- 期刊:
- 影响因子:0
- 作者:Boerneke MA;Hermann T
- 通讯作者:Hermann T
1-Cyclo-hexyl-2-(3-fur-yl)-1H-benzimidazole-5-carboxylic acid.
1-环己基-2-(3-呋喃基)-1H-苯并咪唑-5-甲酸。
- DOI:10.1107/s1600536809031213
- 发表时间:2009
- 期刊:
- 影响因子:0
- 作者:Dibrov,Sergey;Dutta,Sanjay;Hermann,Thomas
- 通讯作者:Hermann,Thomas
{{
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 }}
Thomas C Hermann其他文献
Thomas C Hermann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('Thomas C Hermann', 18)}}的其他基金
Broad-spectrum inhibitors targeting the viral replication promoter conserved in dengue and Zika viruses
针对登革热和寨卡病毒中保守的病毒复制启动子的广谱抑制剂
- 批准号:
10381583 - 财政年份:2021
- 资助金额:
$ 35.39万 - 项目类别:
Broad-spectrum inhibitors targeting the viral replication promoter conserved in dengue and Zika viruses
针对登革热和寨卡病毒中保守的病毒复制启动子的广谱抑制剂
- 批准号:
10194075 - 财政年份:2021
- 资助金额:
$ 35.39万 - 项目类别:
Chemotherapy targeting human thymidylate synthase messenger RNA
针对人胸苷酸合酶信使 RNA 的化疗
- 批准号:
8249765 - 财政年份:2009
- 资助金额:
$ 35.39万 - 项目类别:
Chemotherapy targeting human thymidylate synthase messenger RNA
针对人胸苷酸合酶信使 RNA 的化疗
- 批准号:
8077222 - 财政年份:2009
- 资助金额:
$ 35.39万 - 项目类别:
Chemotherapy targeting human thymidylate synthase messenger RNA
针对人胸苷酸合酶信使 RNA 的化疗
- 批准号:
7727632 - 财政年份:2009
- 资助金额:
$ 35.39万 - 项目类别:
Chemotherapy targeting human thymidylate synthase messenger RNA
针对人胸苷酸合酶信使 RNA 的化疗
- 批准号:
7844811 - 财政年份:2009
- 资助金额:
$ 35.39万 - 项目类别:
Chemotherapy targeting human thymidylate synthase messenger RNA
针对人胸苷酸合酶信使 RNA 的化疗
- 批准号:
8462455 - 财政年份:2009
- 资助金额:
$ 35.39万 - 项目类别:
New Antiviral Therapies for Hepatitis C Infection
丙型肝炎感染的新抗病毒疗法
- 批准号:
7395036 - 财政年份:2007
- 资助金额:
$ 35.39万 - 项目类别:
New Antiviral Therapies for Hepatitis C Infection
丙型肝炎感染的新抗病毒疗法
- 批准号:
7268292 - 财政年份:2007
- 资助金额:
$ 35.39万 - 项目类别:
New Antiviral Therapies for Hepatitis C Infection
丙型肝炎感染的新抗病毒疗法
- 批准号:
7603032 - 财政年份:2007
- 资助金额:
$ 35.39万 - 项目类别:
相似海外基金
How novices write code: discovering best practices and how they can be adopted
新手如何编写代码:发现最佳实践以及如何采用它们
- 批准号:
2315783 - 财政年份:2023
- 资助金额:
$ 35.39万 - 项目类别:
Standard Grant
One or Several Mothers: The Adopted Child as Critical and Clinical Subject
一位或多位母亲:收养的孩子作为关键和临床对象
- 批准号:
2719534 - 财政年份:2022
- 资助金额:
$ 35.39万 - 项目类别:
Studentship
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
- 批准号:
2633211 - 财政年份:2020
- 资助金额:
$ 35.39万 - 项目类别:
Studentship
A material investigation of the ceramic shards excavated from the Omuro Ninsei kiln site: Production techniques adopted by Nonomura Ninsei.
对大室仁清窑遗址出土的陶瓷碎片进行材质调查:野野村仁清采用的生产技术。
- 批准号:
20K01113 - 财政年份:2020
- 资助金额:
$ 35.39万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
- 批准号:
2436895 - 财政年份:2020
- 资助金额:
$ 35.39万 - 项目类别:
Studentship
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
- 批准号:
2633207 - 财政年份:2020
- 资助金额:
$ 35.39万 - 项目类别:
Studentship
The limits of development: State structural policy, comparing systems adopted in two European mountain regions (1945-1989)
发展的限制:国家结构政策,比较欧洲两个山区采用的制度(1945-1989)
- 批准号:
426559561 - 财政年份:2019
- 资助金额:
$ 35.39万 - 项目类别:
Research Grants
Securing a Sense of Safety for Adopted Children in Middle Childhood
确保被收养儿童的中期安全感
- 批准号:
2236701 - 财政年份:2019
- 资助金额:
$ 35.39万 - 项目类别:
Studentship
A Study on Mutual Funds Adopted for Individual Defined Contribution Pension Plans
个人设定缴存养老金计划采用共同基金的研究
- 批准号:
19K01745 - 财政年份:2019
- 资助金额:
$ 35.39万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Structural and functional analyses of a bacterial protein translocation domain that has adopted diverse pathogenic effector functions within host cells
对宿主细胞内采用多种致病效应功能的细菌蛋白易位结构域进行结构和功能分析
- 批准号:
415543446 - 财政年份:2019
- 资助金额:
$ 35.39万 - 项目类别:
Research Fellowships