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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.

项目总结