Chemical Probes on NeuroAIDS

神经艾滋病化学探针

• 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
• 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

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：药物滥用直接导致美国所有HIV-1感染的三分之一。尽管流行病学数据表明阿片类药物滥用是HIV-1感染和向艾滋病发展的危险因素，但积累的证据揭示了在这种病理过程中MU阿片类药物（MOR）和CCR5趋化因子受体之间可能的协同相互作用。因此，对HIV-1感染的阿片类药物增强可能涉及的神经途径的透彻理解至关重要。我们的假设是，含有MOR拮抗剂和CCR5拮抗剂的二价配体可以用作化学探针，以研究阿片类药物滥用增强的HIV-1感染相对于HIV-1感染的相互作用。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显然具有协同作用的基础。二价配体已被证明是表征G蛋白偶联受体（GPCR）蛋白 - 蛋白质蛋白相互作用的强大分子工具，以干扰与这些相互作用相关的正常功能，甚至通过靶向这种相互作用来治疗疾病。我们认为，这种配体不仅可以用作药理探针，以帮助阐明阿片类药物滥用增强的HIV-1感染的机制，并了解由于药物滥用和HIV-1感染引起的痴呆症的神经发生，而且在抑制这种增强的HIV-1感染方面也可能具有治疗性。因此，该项目的长期目标是通过使用这种二价配体阐明阿片类药物增强的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感染相关痴呆症治疗的潜在应用。该提议的具体目的是：1）表征二价 在急性和慢性条件下，在细胞结合和功能测定中的配体； 2）检查二价配体在通过CCR5和MOR-CCR5相互作用阻断HIV-1进入和感染性方面的功效； 3）通过应用二价配体探针研究神经辅助的发病机理。