Molecular Mechanism of HIV Entry Mediated by Chemokine Receptor CCR5

描述(申请人提供)：本提案《趋化因子受体CCR5介导的HIV进入的分子机制》集中于趋化因子受体CCR5(HIV进入共受体)与包括肽仿制在内的多种配体之间的复合体的X射线结构测定。最终目标是利用实验确定的结构进行药物发现，目的是通过基于结构的药物设计(SBDD)方法抑制艾滋病毒细胞进入。CCR5是HIV传播的主要共同受体，而CXCR4嗜性(X4嗜性)病毒在感染后出现与更快的CD4下降和更快的艾滋病进展相关。CCR5作为HIV进入的主要辅助受体，长期以来一直被认为是最重要的药物靶点之一。到目前为止，已经有五种CCR5靶向药物进入临床试验，但只有一种药物马拉韦罗获得了FDA的批准。该药物以及其他CCR5细胞进入抑制剂如何发挥作用的分子细节尚不清楚，将成为拟议研究的重点。拟议的结构研究将使用GPCR网络开发的基因-结构-管道的方法和途径进行。其具体目标是：1)优化CCR5的结构设计，产生用于生物物理和功能研究的高纯度和热稳定的CCR5的大样本；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)通过确定几个化合物的三维结构来了解CCR5的配体结合性质。预计我们的研究产生的结构性知识将导致新的治疗策略的制定，并有助于阻止艾滋病毒/艾滋病在中国和世界其他地方的蔓延。

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.