HIV RNase H natural product inhibitors

HIV逆转录酶（RT）一直是HIV药物开发的一个有吸引力的靶点，20种逆转录酶中有11种 批准的靶向RT DMA聚合酶活性的药物。然而，艾滋病毒的耐药性越来越严重， 严重的临床问题。需要新的治疗方法，特别是针对未解决的艾滋病毒靶点的治疗方法， 例如HIV RT相关的RNase H（RNH）。RNH在抗病毒治疗发现中的探索不足， 发展，并且已经鉴定了非常少的RNH抑制剂（RNHI）。这个研究项目，HIV RNase H天然产物抑制剂，建立在植物细胞培养的新技术基础上，作为新型抗病毒药物的来源。 剂.我们已经鉴定了几种具有亚微摩尔抗病毒活性的天然产物RNHI。的 拟议的研究包括三个项目，旨在开发和优化这些和其他化合物， 从现有的16万个产品库中筛选出来。迭代式研发 该计划结合了来自学术界和工业界的几位调查人员的努力， 在艾滋病毒药物发现和开发方面的经验。项目1，隔离和优化（Baroudy，项目 领导者，Millenia Hope Inc）将从植物细胞培养中分离和纯化天然产物， 在其他项目中开发的基于SAR的半合成优化。项目2，生物化学和 病毒学（匹兹堡大学项目主任Parniak）将对化合物进行生物学表征 生成用于SAR开发的数据的活动，进行详细的作用机制分析，以及 筛选产物文库中的新RNHI化学型。项目3，结构和计算生物学 （Arnold，项目负责人，CABM/Rutgers）将确定RT与RNHI复合的结构，以便沿着使用 使用项目2的数据开发SAR，以预测改进效价的修饰。这样的修改 将在项目1中进行，然后在项目2和3中进行表征。这个迭代过程将持续到2-3 已经选择了具有低nM效力的主要候选物和4-6种备用物进入广泛的临床前研究 考核该研究计划将通过开发新的抗艾滋病毒药物对公共卫生产生重大影响 用于治疗感染了对目前临床上常用的抗HIV病毒的HIV毒株的患者的治疗剂 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.