HIV RNase H Natural Product Inhibitors: Biochemistry and Virology

HIV对临床批准的治疗剂的抗性是日益严重的临床问题。新 需要治疗，特别是那些针对未解决的HIV靶点的治疗，如RT相关的 核糖核酸酶H（RNH）。该项目将有助于验证和临床前开发的RNH抑制剂 通过植物细胞培养物衍生的天然产物的半合成优化制备的RNHI。的目的 该项目是1。进行详细的生物化学和病毒学表征（ 行动）的一系列新的RNHI正在追求的科学家在合作公司，Millenia希望。的 目前的先导化合物在体外对RNH具有亚微摩尔抑制活性，在体外对HIV复制具有亚微摩尔抑制活性， PBMC; 2.筛选150，000个植物来源的部分纯化和纯化的天然产物的文库， 更多的RNHI。命中将在各种二次检测中进行验证， 其他项目组件的优化;以及3.详细描述在 筛选程序。 本项目的工作是整个临床前开发计划的重要组成部分， 与其他项目密切相关（项目1：隔离和优化，项目3：结构和 计算生物学）在整体迭代多项目计划。整个多应用的目标 计划是开发2-3个第一代先导化合物和4-6个具有低nM效价的备用先导化合物。 RNH是HIV复制所必需的，但目前还没有针对这一目标的药物。这项研究计划将 开发一流的靶向RNH的治疗剂，用于治疗HIV感染。因为RNH是 目前使用的艾滋病药物尚未解决的一个新的目标，很可能在这个计划中开发的RNHI将 可用于治疗耐药HIV。

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.