Chemical Probes on NeuroAIDS

神经艾滋病化学探针

基本信息

批准号：
8789943
负责人：
Kurt F Hauser
金额：
$ 19.06万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8789943
关键词：
AIDS neuropathy AIDS/HIV problem Acquired Immunodeficiency Syndrome Acute Affect Affinity Agonist Astrocytes Bilateral Binding Biological Assay CCR5 gene CXCR4 gene Cell Line Cell fusion Cell physiology Cells Chemicals Chemokine (C-C Motif) Receptor 5 Chinese Hamster Ovary Cell Chronic Data Dementia Dimerization Disease Drug abuse Effectiveness Engineering Epidemiology Flow Cytometry Future G-Protein-Coupled Receptors Goals HIV HIV-1 Heroin Human Immune Immunochemistry Infection Inflammatory Lead Ligands Microglia Modeling Molecular Molecular Probes Molecular and Cellular Biology Morphine Naltrexone Neural Pathways Neuropathogenesis Neuropharmacology Opiates Opioid Opioid Receptor Pathogenesis Pathologic Processes Pathway interactions Pharmaceutical Chemistry Property RANTES Risk Factors Role Series Signal Transduction System Testing Therapeutic United States Viral Virion base cell type chemokine receptor clinically relevant desensitization design dimer gp160 high reward high risk innovation macrophage monocyte multidisciplinary next generation novel opioid abuse pharmacophore prevent protein protein interaction public health relevance radioligand receptor receptor binding receptor density single molecule tool

项目摘要

DESCRIPTION: Drug abuse directly contributes to one-third of all HIV-1 infections in the United States. While epidemiological data have demonstrated that opioid abuse is a risk factor for HIV-1 infection and progression to AIDS, accumulating evidence reveals possible synergistic interactions between the mu opioid (MOR) and CCR5 chemokine receptors in this pathologic process. Therefore, a thorough understanding of the neural pathways likely involved in opioid enhancement of HIV-1 infection is essential. Our hypothesis is that bivalent ligands containing both a MOR antagonist and a CCR5 antagonist may serve as chemical probes to study the interaction of these two major receptors with respect to HIV-1 infection enhanced by opioid abuse. The oligomerization of opioid receptors and CCR5 uniquely affects immune cell function and their molecular interactions may underlie their apparently synergistic effects in the CNS. Bivalent ligands have been shown to be powerful molecular tools for characterization of G-protein coupled receptor (GPCR) protein-protein interactions, to interfere with normal function related to these interactions, or even to treat diseases by targeting such interactions. We believe a ligand of this kind may not only serve as a pharmacological probe to help clarify the mechanism of opioid abuse-enhanced HIV-1 infection and understand the neuropathogenesis of dementia due to drug abuse and HIV-1 infection, but may also be therapeutic in repressing this enhanced HIV-1 infection. Therefore, the long-term goals of this project are to elucidate the molecular mechanism of opioid-enhanced HIV-1 infection by using such bivalent ligands, and to explore the potential application of these ligands for the treatment of opioid abuse and HIV-1 infection-related dementia. The specific aims of this proposal are to: 1) characterize the bivalent ligands in cellular binding and functional assays, at both acute and chronic conditions; 2) examine the efficacy of bivalent ligands in blocking HIV-1 entry and infectivity via CCR5 and MOR-CCR5 interactions; and 3) study the pathogenesis of neuroAIDS by applying the bivalent ligand probes.

描述：美国三分之一的 HIV-1 感染是由药物滥用直接造成的。虽然流行病学数据表明阿片类药物滥用是 HIV-1 感染和进展为 AIDS 的危险因素，但越来越多的证据表明 mu 阿片类药物 (MOR) 和 CCR5 趋化因子受体在这一病理过程中可能存在协同相互作用。因此，彻底了解阿片类药物增强 HIV-1 感染可能涉及的神经通路至关重要。我们的假设是，含有 MOR 拮抗剂和 CCR5 拮抗剂的二价配体可以作为化学探针来研究这两种主要受体与阿片类药物滥用增强的 HIV-1 感染之间的相互作用。阿片受体和 CCR5 的寡聚化独特地影响免疫细胞功能，它们的分子相互作用可能是它们在中枢神经系统中明显协同作用的基础。二价配体已被证明是强大的分子工具，可用于表征 G 蛋白偶联受体 (GPCR) 蛋白质-蛋白质相互作用、干扰与这些相互作用相关的正常功能，甚至通过靶向此类相互作用来治疗疾病。我们相信，这种配体不仅可以作为药理学探针，帮助阐明阿片类药物滥用增强HIV-1感染的机制，了解药物滥用和HIV-1感染引起的痴呆的神经发病机制，而且还可能具有治疗作用。抑制这种增强的 HIV-1 感染。因此，该项目的长期目标是利用此类二价配体阐明阿片类药物增强HIV-1感染的分子机制，并探索这些配体在治疗阿片类药物滥用和HIV-1感染方面的潜在应用相关痴呆症。该提案的具体目标是：1）表征二价急性和慢性条件下细胞结合和功能测定中的配体； 2) 检查二价配体通过 CCR5 和 MOR-CCR5 相互作用阻断 HIV-1 进入和感染性的功效； 3)应用二价配体探针研究神经艾滋病的发病机制。