HIV RNase H Natural Product Inhibitors: Biochemistry and Virology

HIV RNase H 天然产物抑制剂：生物化学和病毒学

• 批准号: 7640852
• 负责人: MICHAEL A PARNIAK
• 金额: $ 26.86万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7640852
• 关键词: Address; Antiviral Agents; Back; Biochemical; Biochemistry; Biological Assay; Biological Factors; Cell Line; Class; Clinical; Complex; Computational Biology; Cultured Cells; DNA biosynthesis; DNA chemical synthesis; Data; Development; Dose; Drug Kinetics; End Point; Evaluation; Fluorescence Resonance Energy Transfer; Future; Generations; Goals; Guanosine Monophosphate; HIV; HIV Infections; HIV drug resistance; In Vitro; Libraries; Modification; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Plants; Polymerase; Polymerase Chain Reaction; Preparation; Process; Program Development; Property; Quantitative Structure-Activity Relationship; Research; Resistance; Reverse Transcription; Ribonuclease H; Roentgen Rays; Scientist; Screening procedure; Series; Structure; Therapeutic; Therapeutic Agents; Therapeutic Index; Toxicology; Validation; Viral; Work; analog; design; improved; in vitro Assay; inhibitor/antagonist; novel; novel therapeutics; pre-clinical; programs; response; scale up; small molecule; virology

HIV resistance to clinically approved therapeutics is an increasingly serious clinical problem. New therapeutics are needed, especially those against unaddressed HIV targets, such as RT-associated ribonuclease H (RNH). This project will assist in the validation and preclinical development of RNH inhibitors (RNHIs) prepared by semi-synthetic optimization of plant cell culture derived natural products. The aims of this proposed project are 1. to conduct detailed biochemical and virologic characterizations (mechanism of action) of a series of novel RNHIs being pursued by scientists at the partnering company, Millenia Hope. The current leads have sub-micromolar inhibitory activity against RNH in vitro and against HIV replication in PBMC; 2. to screen a library of 150,000 plant-derived partially purified and purified natural products for additional RNHIs. Hits will be validated in a variety of secondary assays and promising leads will undergo optimizations in other project components; and 3. to characterize in detail the validated hits obtained in the screening program. The work in this project is an essential component of the overall preclinical development program, and is intimately associated with that of the others (Project 1: Isolation & Optimization, and Project 3: Structural and Computational Biology) in the overall iterative multi-project program. The goal of the entire multi-application program is to develop 2-3 first generation leads and 4-6 back-up leads with low nM potencies. RNH is essential for HIV replication, yet there are no drugs directed at this target. This research program will develop a first-in-class therapeutic agent targeting RNH for use in the treatment of HIV infection. As RNH is a novel target unaddressed by currently used HIV drugs, it is likely that RNHIs developed in this program will be useful for the treatment of drug-resistant HIV.

HIV对临床批准的治疗药物的耐药性是一个日益严重的临床问题。新的 治疗是必要的，特别是针对未解决的艾滋病毒目标的治疗，如RT-相关 核糖核酸酶H(RNH)。该项目将有助于RNH抑制剂的验证和临床前开发。 (RNHIs)由植物细胞培养衍生的天然产物半合成优化而成。的目标是 这项拟议的项目是1.进行详细的生化和病毒学特征(机制 合作公司Millenia Hope的科学家们正在研究一系列新颖的RNHI。这个 电流引线在体外对RNH具有亚微摩尔抑制活性，对HIV复制具有抑制作用 Pbmc；2.筛选150,000个植物来源的部分纯化和纯化的天然产物库，用于 额外的RNHI。HITS将在各种二次分析中得到验证，有希望的线索将经历 其他项目组件中的优化；以及3.详细描述在 筛查计划。 该项目的工作是整个临床前开发计划的重要组成部分，并且是 与其他项目密切相关(项目1：隔离和优化，项目3：结构和优化 计算生物学)在整个迭代多项目方案中。整个多应用程序的目标是 计划开发2-3条第一代导线和4-6条低NM电势的备用导线。 RNH对于艾滋病毒复制是必不可少的，但目前还没有针对这一目标的药物。这项研究计划将 开发一种针对RNH的一流治疗剂，用于治疗HIV感染。就像RNH一样 这是目前使用的艾滋病毒药物尚未解决的一个新靶点，在该计划中开发的RNHIs很可能将 对于抗药性艾滋病毒的治疗是有用的。