RNA TARGETS FOR ANTIRETROVIRAL THERAPY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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基因变异迅速出现，帮助病毒逃避宿主免疫和多药疗法，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的靶点的必要性仍然非常高。为此，我们解决了HIV-1RNA基因组5‘-非翻译区的RNA茎环结构SL1的高分辨率核磁共振结构。这种结构具有非常保守的基序，即一个富含G的内环(GRIL)，它参与了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的核磁共振结构来进行结合SL1的小分子的计算筛选。计算对接是使用魔多软件进行的，绑定姿势是使用嵌合体检查的。使用核磁共振和荧光技术对计算命中进行了实验验证。

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.