Targeting RNA Binding and Nuclear Export of HIV Rev

描述(由申请人提供)：REV是一种对HIV复制必不可少的小的碱性蛋白质。该计划概述了一个全面的计划，以回答有关REV功能机制的重要问题，并确定REV-RRE相互作用的小分子抑制剂，为开发抗HIV治疗药物提供基础。REV与病毒mRNA中一个称为REV反应元件的区域结合，形成一个寡聚复合体，靶向从核输出的mRNA，这构成了新的抗病毒治疗的可行靶点。 该计划由六个相互关联的项目和核心组成部分组成，应用各种实验方法研究REV的RNA结合和核输出功能，并确定这些功能的抑制剂。我们将使用体外试验表征REV与RRE RNA的相互作用，并开发鉴定REV抑制剂的筛选方法。将应用于理解和定位REV的学科包括细胞生物学、生物化学、结构生物学、生物物理学和合成有机化学。使用这种广泛但集成良好的方法，我们将解决关于REV功能机制的关键剩余问题，解决REV作为治疗靶点的有效性，并产生小分子先导化合物，以刺激涉及这一重要但未被充分利用的HIV靶点的药物发现努力。

DESCRIPTION (provided by applicant): Rev is a small basic protein that is essential for HIV replication. This program outlines a comprehensive plan to answer important questions about the mechanism of Rev function, and to identify small molecule inhibitors of Rev-RRE interactions that provide the basis for developing anti-HIV therapeutics. Rev associates with a region in the viral mRNA termed the Rev Responsive Element to form an oligomeric complex that targets the mRNA for export from the nucleus, which constitutes a viable target for novel antiviral therapies. This program consists of six interrelated Projects and Core components that apply a variety of experimental approaches to study the RNA binding and nuclear export functions of Rev and to identify inhibitors of those functions. We will characterize the interactions of Rev with the RRE RNA using in vitro assays and develop screening methodologies for identification of Rev inhibitors. The disciplines that will be applied to understanding and targeting Rev include cell biology, biochemistry, structural biology, biophysics, and synthetic organic chemistry. Using this broad but well-integrated approach, we will address key remaining questions about the mechanism of Rev function, address the validity of Rev as a therapeutic target, and generate small molecule lead compounds that will stimulate drug discovery efforts involving this important but under-exploited HIV target.