HIV RNase H Natural Product Inhibitors: Isolation and Optimization

我们的目标是鉴定和优化植物来源的小分子，以抑制HIV RT相关的 RNaseH(RNH)活性，HIV干预的新靶点。本项目的总体目标是推荐 从10,000个馏分(第一个程序)的初始筛选中开发2-3个化合物(CD)和 推荐4-6张CD(备份计划)，用于筛选植物衍生库的其余部分(150,000张 分数)。第一代CD应该达到50 nm或更好的IC50，而第二代CD应该达到50 nm或更好 应具有个位数的nm IC50。这些化合物应该有效地抑制艾滋病毒毒株 对目前的药物具有抗药性。RNH抑制剂(RNHI)将利用生化和病毒学数据进行优化 最初是利用从X射线结晶学获得的计算和结构信息 RT-RNHI复合体的研究(请参阅本RFA中的其他项目)，以允许合理设计类似物 将是合成的或半合成的。如果采用半综合的方法，我们可以使用 我们用50克L生物反应器来产生克量的起始材料，让我们产生一个小型的文库 类比。此外，还将利用组合合成和并行合成来增加某些分子 潜在铅的数量和化学多样性。我们将坚持以下既定指导方针 利平斯基的五条法则增加了我们获得类药物分子的机会。类比表明 活性的提高将受到ADME/PK研究的影响，以选择药物样先导。这一过程将 重复进行，直到我们达到表4中描述的CD的配置文件。我们还想包括另一个 在我们的RNHI药物发现中的方法。我们将利用我们的一些线索产生的代谢物 作为鉴定RNHI的新化学类型的来源。我们对结果感到非常鼓舞，我们 到目前为止获得(Tablel)。在生化和基于细胞的值之间有很强的相关性，一些 有一个IC50；lt；1uM与优秀的治疗指数&gt；200。这是向前迈出的重要一步 确定和发展农村卫生保健机构。这是对我们到目前为止开发的植物细胞培养技术的致敬。 一个高度多样化的文库，来自2200多种植物，代表284个植物科， 这是由于次级代谢物产生的高度重复性所决定的。这个项目有巨大的 在提供一类新的艾滋病毒药物方面的潜在影响。

Our objective is to identify and optimize plant derived small molecules for the inhibition of HIV RT-associated RNase H (RNH) avtivity, a novel target for HIV intervention. The overall goal of this poject is to recommend 2-3 compounds for development (CD) from the initial screen of 10,000 fractions (1st program) and recommend 4-6 CDs (back up program) from screening the rest of the plant derived library (150,000 fractions). The first generation CDs should attain an IC50 of 50 nm or better while second generation CDs should have single digit nm IC50. These compounds should be effective in ihibiting HIV strains that are resistant to current drugs. RNH inhibitors (RNHI) will be optimized using biochemical and virologic data initially followed by utilizing computanional and structural information obtained from X-ray crystallographic studies of RT-RNHI complexes (see other projects within this RFA) to allow rational design of analogs that will be either synthesized or semi-synthesized. In case a semi-synthetic approach is adopted, we can use our 50 L bioreactor to produce gram quantities of the starting material to allow us to generate a small library of analogs. In addition, combinatorial and parallel synthesis will be utilized for some molecules to increase both the quantity and chemical diversity of potential leads. We will adhere to established guidlines such as the Lipinski "Rule of five" to increase our chances of obtaining drug like molecules. Analogs that show improved acivity will be subjected to ADME/PK studies in order to select for drug like leads. This process will be repeated until we achieve the profile of a CD described in Table 4. We would like to include yet another approach in our drug discovery of RNHI. We will exploit the generation of metabolites of some of our leads as a source of new chemotypes for identifyiing RNHI. We are very encouraged by the results that we obtained so far (Tablel). There is a strong correlation between the biochemical and cell-based values, some having an IC50<1uM with an excellent therapeutic Index >200. This represents a major step forward in identifying and developing RNHIs. It is a tribute to the plant cell culture technology that we developed so far. A highly diverse library that originated from more than 2200 plant species, representing 284 plant families, that is charecarized by a high reproducibility of secondary metabolite production. This project has enormous potential impact in delivering a new class of HIV drugs.