STRUCTURAL STUDIES OF HIV-1 RT AND RNAP

HIV-1 RT 和 RNAP 的结构研究

• 批准号: 8170617
• 负责人: EDWARD ARNOLD
• 金额: $ 0.57万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8170617
• 关键词: Anti-HIV Agents; Antibiotics; Bacterial RNA; Behavior; Binding; Complex; Computer Retrieval of Information on Scientific Projects Database; Crystallography; DNA-Directed RNA Polymerase; Data; Development; Drug Binding Site; Drug Delivery Systems; Funding; Grant; HIV-1; Institution; Knowledge; Lead; Nucleic Acids; Nucleosides; Pharmaceutical Preparations; Research; Research Personnel; Resolution; Resources; Ribonuclease H; Roentgen Rays; Screening procedure; Source; Structure; United States National Institutes of Health; base; design; improved; inhibitor/antagonist; non-nucleoside reverse transcriptase inhibitors; nucleotide analog; three dimensional structure

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The development of improved inhibitors of a drug target can be aided by detailed knowledge of its three-dimensional structure. Using data collected at BNL-NSLS, bemline X25 we plan to determine structures of HIV-1 RT in the presence and absence of both RNA/DNA and DNA/DNA in complex with a variety of inhibitors including: nucleoside/nucleotide analogs (NRTIs), specific RNase H inhibitors (RNHIs), and non-nucleoside RT inhibitors (NNRTIs) that would enable structure-based design of potential new anti-HIV drugs. Additionally we plan to use high resolution X-ray crystal structures of HIV-1 RT to carry out a drug fragment cocktail screening project designed to identify new lead compounds for existing drug-binding sites as well as discovering new inhibitor binding pockets. We also plan to pursue structural studies of bacterial RNA polymerase (RNAP) in complexes with various nucleic acid constructs and antibiotics to expand our understanding of the inhibitory behavior of these compounds on RNAP function.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 对药物靶点三维结构的详细了解可以帮助开发改进的药物靶点抑制剂。使用 BNL-NSLS、bemline X25 收集的数据，我们计划确定在存在或不存在 RNA/DNA 和 DNA/DNA 与多种抑制剂复合的情况下 HIV-1 RT 的结构，这些抑制剂包括： 核苷/核苷酸类似物 (NRTI) 、特异性 RNase H 抑制剂 (RNHI) 和非核苷 RT 抑制剂 (NNRTI)，这将使潜在的新型抗 HIV 药物的基于结构的设计成为可能。此外，我们计划使用 HIV-1 RT 的高分辨率 X 射线晶体结构来开展药物片段鸡尾酒筛选项目，旨在识别现有药物结合位点的新先导化合物以及发现新的抑制剂结合袋。我们还计划对细菌 RNA 聚合酶 (RNAP) 与各种核酸结构和抗生素的复合物进行结构研究，以扩大我们对这些化合物对 RNAP 功能的抑制行为的理解。