Molecular Mechanism of HIV Entry Mediated by Chemokine Receptor CCR5

描述（由申请人提供）：本课题“趋化因子受体CCR5介导的HIV进入分子机制”主要研究趋化因子受体CCR5（一种HIV进入共受体）与多种配体（包括拟肽物）之间复合物的x射线结构测定。最终目标是利用实验确定的结构，利用基于结构的药物设计（SBDD）方法进行旨在抑制HIV细胞进入的药物发现。CCR5是负责HIV传播的主要共受体，而在感染后期出现的CXCR4-tropic （X4-tropic）病毒与CD4更快下降和更快发展为艾滋病相关。作为HIV进入的主要共受体，CCR5一直被认为是最重要的药物靶点之一。到目前为止，已有5种CCR5靶向药物进入临床试验，但只有一种药物获得了FDA的批准，即Maraviroc。这种药物以及其他CCR5细胞进入抑制剂如何起作用的分子细节尚不清楚，这将是拟议研究的重点。拟议的结构研究将使用由GPCR网络开发的基因到结构管道的方法和途径进行。具体目标是：1)优化CCR5构建体设计，生成大量高纯度、热稳定的CCR5样品，用于生物物理和功能研究；2)设计和合成可用于稳定CCR5和探测配体-受体相互作用的化学工具；3)通过确定几种配合物的三维结构，了解CCR5配体的结合特性。预期我们的研究所产生的结构知识将导致新的治疗策略的发展，并有助于阻止艾滋病毒/艾滋病流行病在中国和世界其他地方的增长。

DESCRIPTION (provided by applicant): This proposal "Molecular Mechanism of HIV Entry Mediated by Chemokine Receptor CCR5" is focused on X-ray structure determination of complexes between chemokine receptor CCR5, an HIV entry co- receptor, and a variety of ligands including peptidomimetics. The ultimate goal is to use the experimentally determined structure to carry out drug discovery aimed at inhibiting HIV cell entry using structure-based drug design (SBDD) approaches. CCR5 is the primary co-receptor responsible for HIV transmission, while emergence of CXCR4-tropic (X4-tropic) viruses later in infection correlates with a more rapid CD4 decline and a faster progression to AIDS. As the predominant co-receptor for HIV entry, CCR5 has long been taken as one of the most important drug targets. Five CCR5 targeted drugs to date have been brought to clinical trial, but only one, Maraviroc, has been approved by FDA. Molecular details of how this drug as well as other CCR5 cell entry inhibitors works are not understood and will be a focus of the proposed study. The proposed structural studies will be carried out using methods and approaches of the Gene-to-Structure-Pipeline that was developed by the GPCR Network. The specific aims are: 1) Optimize the CCR5 construct design to generate large samples of highly purified and thermally stabilized CCR5 for biophysical and functional studies; 2) Design and synthesize chemical tools that can be used to stabilize CCR5 and to probe ligand-receptor interactions; 3) Develop an understanding of CCR5 ligand binding properties by determining the 3D structures of several complexes. It is expected that structural knowledge generated by our studies will lead to the development of new therapeutic strategies and help in stopping the growth of the HIV/AIDS epidemic in China and elsewhere in the world.