Defining Inhibitory Mechanisms of Novel CCRS-targeted Microbicide Candidates

定义新型 CCRS 靶向杀菌剂候选物的抑制机制

基本信息

批准号：
7418076
负责人：
DONALD E MOSIER
金额：
$ 53.24万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-06 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7418076
关键词：
AIDS/HIV problem Animal Model Antiviral Agents Area Binding CCL3L1 gene CCR5 gene Cell Differentiation process Cell surface Cells Cellular biology Chemokine (C-C Motif) Receptor 5 Class Collaborations Data Dose Endocytosis GTP-Binding Proteins Genetic Polymorphism Genotype Goals HIV-1 Human Infection Kinetics Knowledge Lateral Ligands Link Mediating Membrane Modeling Molecular Probes Mutate Normal Cell Numbers Personal Satisfaction Population Predisposition Primates Process Production Promoter Regions Protein Biosynthesis RANTES Range Rate Recombinants Recycling Research Design Route Safety Series Signal Pathway Signal Transduction Site Structural Genes T-Lymphocyte Testing Tissues Variant Virus analog base chemokine cost density design dimer improved inhibitor/antagonist macrophage microbicide migration monocyte mutant novel prevent programs protein degradation receptor receptor internalization research study simian human immunodeficiency virus trafficking vaginal transmission

项目摘要

Project 1 - The goal of Project 1 is to define the mechanism of action of three new chemokine analogues with potent activity in blocking HIV-1 entry via CCR5. These fully recombinant molecules display three distinct activity profiles: (group I) CCR5 blockade without signaling activity or receptor internalization; (group II), CCR5 rapid internalization with signaling activity; and (group III), moderate CCR5 internalization and blockade without signaling activity. These new molecules have significant potential advantages in terms of safety and cost of production ..over currenynh[b^ fwither, irrtpr.pvejTients.,p,n these bahdidate'microbicides requires more detailed knowledge of their mechanisms of action. We will define the route to intracellular sequestration for group II molecules, and compare with that of the group III molecules. We will examine a number of hypotheses to explain prolonged antiviral activity in the absence of intracellular receptor sequestration (group I) or with moderate internalization (group III), including changes in CCR5 dimer formation, altered receptor localization in the membrane, allosteric effects, and receptor internalization independent of G-protein-linked signaling. We will also examine the impact of CCR5, CCL5, and CCL3L1 genetic polymorphisms on CCR5 protein synthesis and turnover rate. These studies are designed to investigate variability in the susceptibility of primary target cells from normal human donors to each of the new inhibitors. We will also use a panel of mutant CCR5 molecules to examine structural correlates of activity. We will use this information on mechanism and target cell variability to develop new molecules with even better activity profiles, and we will perform coordinated experiments with other projects in this Program to relate our findings in cell-based models to the effects of current and new CCR5 inhibitors in tissue explant and whole animal models. This approach will generate better and safer CCR5 inhibitors that can be produced on a scale suitable for stopping the spread of HIV/AIDS in the most-impacted areas.

项目1-项目1的目标是定义三个新趋化因子类似物的作用机理通过CCR5阻止HIV-1进入的有效活性。这些完全重组分子显示三个不同的活动曲线：（第I组）CCR5阻断而没有信号活性或受体内在化；（团体 ii），CCR5具有信号活性的快速内在化；（第三组），中等CCR5内在化和没有信号活动的封锁。这些新分子就安全性和生产成本。这些bahdites'microbicides需要对其作用机理进行更详细的了解。我们将定义第II组分子的细胞内螯合途径，并与III组的途径进行比较分子。我们将检查许多假设，以解释在没有的情况下延长的抗病毒活性细胞内受体隔离（I组）或中等内在化（III组），包括变化 CCR5二聚体形成，受体定位改变了膜中，变构作用和受体内部化与G蛋白相关的信号无关。我们还将检查CCR5，CCL5的影响和CCL3L1遗传多态性在CCR5蛋白合成和周转率上。这些研究是旨在调查主要靶细胞从正常人类供体到的敏感性的变异性每个新抑制剂。我们还将使用一组突变的CCR5分子来检查结构活动相关。我们将使用有关机制和目标细胞变异性的此信息来开发新的具有更好活性曲线的分子，我们将与其他项目进行协调的实验在此程序中，将我们的基于细胞模型的发现与当前和新CCR5抑制剂的影响联系起来在组织外植体和整个动物模型中。这种方法将产生更好，更安全的CCR5抑制剂可以以适合在最受影响的地区停止艾滋病毒/艾滋病的传播的尺度生产。