HIV RNase H natural product inhibitors

艾滋病毒逆转录酶(RT)一直是艾滋病毒药物开发的一个有吸引力的目标，20种药物中有11种 针对RT-DMA聚合酶活性的批准药物。然而，艾滋病毒的抗药性越来越强。 严重的临床问题。需要新的疗法，特别是那些针对未解决的艾滋病毒目标的疗法， 如HIV RT相关核糖核酸酶H(RNH)。RNH在抗病毒治疗方面的开发不足， 目前已确定的RNH抑制剂(RNHI)很少。这项研究计划，艾滋病毒核糖核酸酶 H天然产物抑制剂，建立在植物细胞培养的新技术基础上，作为新型抗病毒的来源 探员们。我们已经鉴定出几种天然产物RNHI具有亚微摩尔的抗病毒活性。这个 拟议的研究包括三个项目，旨在开发和优化这些化合物和其他化合物，以 通过筛选现有的160,000个产品库来确定。迭代的研究与开发 该计划结合了几位来自学术界和工业界的研究人员的努力，并具有相当大的 有艾滋病药物发现和开发经验。项目1，隔离和优化(Baroudy，项目 Leader，Millenia Hope Inc.)将从植物细胞培养物中分离和纯化天然产品，并进行 基于合成孔径雷达的半综合优化是在其他项目中开展的。项目2，生物化学和 病毒学(帕尼亚克，匹兹堡大学项目主任)将描述化合物的生物学特性 活动，以生成用于特别行政区发展的数据，进行详细的行动机制分析，以及 筛选新的RNHI化学类型的产品库。项目3，结构和计算生物学 (CABM/罗格斯大学项目负责人Arnold)将确定RT与RNHI的复杂结构，以便与RNHI一起使用 利用项目2中的数据来开发一种预测修改以提高效力的SAR。这样的修改 将在项目1中完成，然后在项目2和3中确定特征。这一迭代过程将持续到2-3 已选择主要候选者和4-6个NM效力较低的备份进入广泛的临床前阶段 评估。该研究项目将通过开发新的抗艾滋病毒药物对公共健康产生重大影响 用于治疗感染目前临床耐药的艾滋病毒株的患者的治疗药物 吸毒。

HIV reverse transcriptase (RT) has been an attractive target for HIV drug development, with 11 of the 20 approved drugs targeting RT DMA polymerase activity. However, HIV drug resistance is an increasingly serious clinical problem. New therapeutics are needed, especially those against unaddressed HIV targets, such as HIV RT-associated RNase H (RNH). RNH is underexplored for antiviral therapeutic discovery and development, and very few RNH inhibitors (RNHI) have been identified. This research program, HIV RNase H Natural Product Inhibitors, builds on a novel technology for plant cell culture as a source of novel antiviral agents. We have already identified several natural product RNHI with submicromolar antiviral activity. The proposed studies comprise three projects designed to develop and optimize these and other compounds to be identified from screening an existing 160,000 product library. The iterative research and development program combines the efforts of several investigators from academia and industry with considerable experience in HIV drug discovery and development. Project 1, Isolation and Optimization (Baroudy, Project Leader, Millenia Hope Inc) will isolate and purify natural products from plant cell cultures and carry out semisynthetic optimizations based on SAR developed in the other projects. Project 2, Biochemistry and Virology (Parniak, Program Director, University of Pittsburgh) will characterize the compounds for biological activity to generate data for use in SAR development, conduct detailed mechanism of action analysis, and screen the product library for new RNHI chemotypes. Project 3, Structural and Computational Biology (Arnold, Project Leader, CABM/Rutgers) will determine structures of RT complexed with RNHI for use along with data from Project 2 to develop an SAR to predict modifications to improve potency. Such modifications will be made in Project 1, then characterized in Projects 2 & 3. This iterative process will continue until 2-3 lead candidates and 4-6 backups with low nM potency have been selected to enter extensive preclinical assessment. The research program will have significant impact on public health by developing new anti-HIV therapeutics for use in the treatment of patients infected with HIV strains resistant to the current clinically used drugs.