Molecular Mechanism of HIV Entry Mediated by Chemokine Receptor CCR5

趋化因子受体CCR5介导的HIV侵入的分子机制

基本信息

批准号：
8323598
负责人：
BEILI WU
金额：
$ 13.5万
依托单位：
SHANGHAI INSTITUTE OF MATERIA MEDICA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-15 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8323598
关键词：
AIDS/HIV problem Academy Acquired Immunodeficiency Syndrome Address Binding Biology CCR5 gene CXCR4 gene Cells Chemicals Chemistry Chemokine (C-C Motif) Receptor 5 China Chinese People Clinical Trials Collaborations Complement Complex Crystallization Data Development Diffusion Drug Delivery Systems Drug Design Epidemic Exclusion FDA approved Feedback Fluorescence G-Protein-Coupled Receptors Genes Glycoproteins Goals Growth HIV HIV Envelope Protein gp120 HIV Receptors HIV-1 Human Infection Institutes Knowledge Laboratories Lead Ligand Binding Ligands Lipids Marketing Materia Medica Mediating Membrane Fusion Methods Metric Molecular Molecular Mechanisms of Action Peptides Pharmaceutical Preparations Phase Production Property Protein Structure Initiative Proteins Research Institute Risk Roentgen Rays Sampling Sampling Studies Science Screening procedure Structure T-20 V3 Loop Virus Work base chemokine chemokine receptor combat design design and construction drug discovery expectation experience inhibitor/antagonist meetings mimetics novel novel therapeutics peptidomimetics radioligand receptor structural biology three dimensional structure tool transmission process

项目摘要

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. PUBLIC HEALTH RELEVANCE: The proposed project attempts to understand the ligand binding properties of the HIV co- receptor CCR5. Studies will then focus on using this knowledge to develop new therapeutic strategies against the virus with the expectation that this will help in combating the Global HIV/AIDS epidemic.

描述（由申请人提供）：该提案“由趋化因子受体CCR5介导的HIV进入的分子机制”集中于X射线结构的确定趋化因子受体CCR5之间的复合物，HIV进入受体和包括肽匹配包括肽疗法在内的多种配体。最终目标是使用实验确定的结构进行旨在使用基于结构的药物设计（SBDD）方法抑制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，CXCR4-热带（X4-纤维化）病毒的出现与CD4的下降更快，并且更快地向AIDS发展相关。作为艾滋病毒进入的主要共受体，CCR5长期以来一直被视为最重要的药物靶标之一。迄今为止，已将五种CCR5靶向药物用于临床试验，但只有一种Maraviroc已获得FDA的批准。该药物以及其他CCR5细胞进入抑制剂作品的分子细节尚不了解，这将是拟议研究的重点。提出的结构研究将使用由GPCR网络开发的基因对结构二管的方法和方法进行。具体目的是：1）优化CCR5构造设计，以生成高纯化和热稳定的CCR5的大型样品，用于生物物理和功能研究； 2）设计和合成化学工具，可用于稳定CCR5并探测配体受体相互作用； 3）通过确定几种复合物的3D结构来发展对CCR5配体结合特性的理解。可以预期，我们的研究产生的结构知识将导致新的治疗策略的发展，并有助于阻止中国和世界其他地方的艾滋病毒/艾滋病流行的增长。公共卫生相关性：拟议的项目试图了解HIV CO-CON-CON-CCR5的配体结合特性。然后，研究将集中于利用这些知识来开发针对病毒的新治疗策略，并期望这将有助于打击全球艾滋病毒/艾滋病流行病。