RNA TARGETS FOR ANTIRETROVIRAL THERAPY

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 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遗传变异的迅速出现，帮助病毒逃避宿主免疫和多药疗法，人们仍然非常关注。因此，开发新的抗HIV治疗药物和寻找新靶点的需求仍然非常高。为此，我们已经解决了一个高分辨率的NMR结构的RNA茎环结构，SL 1，从5 '非翻译区的HIV-1 RNA基因组。该结构具有高度保守的基序，即富含G的内环（GRIL），并且它参与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SL 1 NMR结构来进行结合SL 1的小分子的计算筛选。使用MORDOR软件进行计算对接，并使用Chimera检查结合位姿。使用NMR，表面等离子体共振和荧光技术的实验验证计算命中。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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 a 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, surface plasmon resonance and fluorescent techniques.