Bivalent Ligands as Chemical Probes to Study Opioid Abuse-enhanced HIV Infection

二价配体作为化学探针研究阿片类药物滥用增强的 HIV 感染

基本信息

批准号：
9924466
负责人：
Kurt F Hauser
金额：
$ 56.79万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9924466
关键词：
Acquired Immunodeficiency Syndrome Acute Adopted Affect Affinity Astrocytes Binding Biological Assay Biological Process CCR5 gene Cell Line Cell fusion Cell physiology Cells Chemicals Chronic Crystallization Cyclic AMP Dimerization Disease Docking Drug abuse FDA approved Flow Cytometry Foundations Future G-Protein-Coupled Receptors GTP Binding HIV HIV Envelope Protein gp120 HIV Infections HIV-1 Heroin Human Immune Immunochemistry Infection LIMK1 gene Laboratories Length Ligands MAP Kinase Gene Mediating Microglia Modeling Modification Molecular Molecular Probes Molecular Structure Molecular and Cellular Biology Morphine Naltrexone Neural Pathways Neuropharmacology Opiate Addiction Opioid Opioid Antagonist Pathologic Processes Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Positioning Attribute Risk Factors Role Route Screening Result Signal Pathway Solid Structure Substance abuse problem System Testing Therapeutic Intervention United States Universities V3 Loop Virginia Virion base cell type chemical synthesis chemokine receptor clinically relevant cofilin comorbidity design dimer effectiveness testing epidemiologic data gp160 immune function macrophage molecular modeling monocyte mu opioid receptors multidisciplinary neuroAIDS new therapeutic target novel opioid abuse pharmacophore prevent protein protein interaction radioligand receptor receptor binding receptor density receptor function single molecule skills targeted treatment therapeutic development therapy development tool

项目摘要

Project Summary Drug abuse directly contributes to one-third of all HIV infections in the United States. Epidemiological data have demonstrated that opioid abuse is a significant risk factor for HIV infection and progression to AIDS while 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 infection is essential. The putative dimerization of the mu opioid and CCR5 receptors 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. As a proof-of- concept, our recently developed bivalent ligand carrying MOR-CCR5 dual antagonist pharmacophores has shown significantly higher inhibitory effect on HIV-1 invasion in human macrophages and astrocytes compared to a simple mixture of the two antagonists. Our hypothesis is that bivalent ligands containing both an MOR antagonist and a CCR5 antagonist may serve as chemical probes to study the interaction of these receptors with respect to HIV infection enhanced by opioid abuse. We believe a ligand of this kind may serve as a pharmacological probe to help clarify the molecular mechanism of opioid abuse enhanced HIV infection, and help establish this evolving protein-protein interaction model as a potential target for therapeutic intervention in opioid abuse enhanced neuroAIDS. The specific aims of this proposal are to: 1) design and synthesize novel bivalent ligands containing both an MOR antagonist and a CCR5 antagonist as dual pharmacophores by applying crystal structures of ligand bound MOR and CCR5 proteins, molecular modeling, and chemical synthesis; 2) characterize these bivalent ligands with receptor binding and functional assays; and 3) examine the relative efficacy of bivalent ligands in blocking HIV entry and infectivity via CCR5, and CCR5-MOR interactions. We believe such an effort will build the foundation to understand such a complicated biological process, define a novel therapeutic target to treat neuroAIDS, and facilitate future treatment development for the disease.

项目摘要药物滥用直接导致美国所有艾滋病毒感染的三分之一。流行病学数据已经证明阿片类药物滥用是艾滋病毒感染和艾滋病进展的重要危险因素积累的证据揭示了MU阿片类药物（MOR）和CCR5之间可能的协同相互作用在此病理过程中的趋化因子受体。因此，对神经途径有透彻的理解可能参与艾滋病毒感染的阿片类药物增强是必不可少的。 MU阿片类药物的推定二聚化 CCR5受体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的基础 CNS显然具有协同作用。二价配体已被证明是强大的分子工具 G蛋白偶联受体（GPCR）蛋白质蛋白相互作用的表征，以干扰正常与这些相互作用相关的功能，甚至通过靶向这种相互作用来治疗疾病。作为证明概念，我们最近开发的二价配体携带MOR-CCR5双重拮抗剂药算术具有比较显示对人类巨噬细胞和星形胶质细胞中HIV-1侵袭的抑制作用明显更高与两个拮抗剂的简单混合物。我们的假设是含有MOR的二价配体拮抗剂和CCR5拮抗剂可以用作研究这些受体相互作用的化学探针关于阿片类药物滥用增强的艾滋病毒感染。我们相信这种配体可能会充当药理学探针，以帮助阐明阿片类药物滥用的分子机制增强了HIV感染，并帮助建立这种不断发展的蛋白质 - 蛋白质相互作用模型作为治疗干预的潜在目标阿片类药物滥用增强了神经助剂。该建议的具体目的是：1）设计和合成新颖二价配体含有MOR拮抗剂和CCR5拮抗剂作为双重药剂算体应用配体结合MOR和CCR5蛋白的晶体结构，分子建模和化学合成; 2）用受体结合和功能测定法表征这些二价配体； 3）检查二价配体在通过CCR5和CCR5-MOR阻断HIV进入和感染性方面的相对功效互动。我们认为，这样的努力将建立基础，以了解如此复杂的生物学过程，定义一个新型的治疗靶标，用于治疗神经助剂，并促进未来的治疗开发疾病。