RNA TARGETS FOR ANTIRETROVIRAL THERAPY

抗逆转录病毒治疗的 RNA 靶点

• 批准号: 8170539
• 负责人: THOMAS L JAMES
• 金额: $ 0.72万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 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/8170539
• 关键词: 5' Untranslated Regions; Binding; Chimera organism; Computer Retrieval of Information on Scientific Projects Database; Computer software; Dimerization; Docking; Funding; Genome; Grant; HIV-1; Highly Active Antiretroviral Therapy; Immunity; Institution; Life Cycle Stages; Pharmaceutical Preparations; RNA; Research; Research Personnel; Resolution; Resources; Screening procedure; Source; Staging; Structure; Techniques; Therapeutic; United States National Institutes of Health; Virus; antiretroviral therapy; genetic variant; small molecule; stem; success

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. Despite the success of highly active anti-retroviral therapy (HAART), great concern remains due to rapid emergence of new HIV-1 genetic variants that help the virus escape host immunity and multidrug therapies. Hence, the need to develop new anti-HIV therapeutic drugs and search for new targets remains very high. To this end, we have solved a high-resolution NMR structure for an RNA stem-loop structure, SL1, from the 5'-untranslated region of the HIV-1 RNA genome. This structure has strongly conserved motif, a G-rich internal loop (GRIL), and it is involved in the dimerization of the HIV-1 RNA genome and RNA packaging, two crucial stages of the HIV-1 life cycle. We are using the SL1 NMR structure to carry out a computational screening of small molecules binding SL1. Computational docking is carried out using the MORDOR software, and binding poses are examined using Chimera. Computational hits are verified experimentally using NMR and fluorescent techniques.

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。 尽管高效抗逆转录病毒疗法 (HAART) 取得了成功，但由于新的 HIV-1 基因变异的迅速出现，帮助病毒逃避宿主免疫和多药治疗，人们仍然非常担忧。因此，开发新的抗艾滋病毒治疗药物和寻找新靶点的需求仍然非常高。为此，我们从 HIV-1 RNA 基因组的 5'-非翻译区解析出了 RNA 茎环结构 SL1 的高分辨率 NMR 结构。该结构具有高度保守的基序，即富含 G 的内环 (GRIL)，它参与 HIV-1 RNA 基因组的二聚化和 RNA 包装，这是 HIV-1 生命周期的两个关键阶段。我们正在使用 SL1 NMR 结构对结合 SL1 的小分子进行计算筛选。使用 MORDOR 软件进行计算对接，并使用 Chimera 检查结合姿势。使用核磁共振和荧光技术对计算结果进行实验验证。