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.

Public Health Relevance

Morphine, along with heroin and other opioids, has been shown to enhance HIV-1 infection. This proposal will apply novel chemical probes to investigate the molecular mechanism of opioid abuse enhanced HIV-1 infection in an effort to understand the neuropathogenesis of dementia due to drug abuse and HIV-1 infection. We will use the multidisciplinary tools of neuropharmacology, molecular and cellular biology, medicinal chemistry, and immunochemistry to explore the mechanism and provide a basis for developing appropriate treatments.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Exploratory/Developmental Grants (R21)
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NeuroAIDS and other End-Organ Diseases Study Section (NAED)
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Rapaka, Rao
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Virginia Commonwealth University
Schools of Pharmacy
United States
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Wang, Huiqun; Zaidi, Saheem A; Zhang, Yan (2017) Binding mode analyses of NAP derivatives as mu opioid receptor selective ligands through docking studies and molecular dynamics simulation. Bioorg Med Chem 25:2463-2471
Arnatt, Christopher K; Falls, Bethany A; Yuan, Yunyun et al. (2016) Exploration of bivalent ligands targeting putative mu opioid receptor and chemokine receptor CCR5 dimerization. Bioorg Med Chem 24:5969-5987
Hahn, Yun K; Paris, Jason J; Lichtman, Aron H et al. (2016) Central HIV-1 Tat exposure elevates anxiety and fear conditioned responses of male mice concurrent with altered mu-opioid receptor-mediated G-protein activation and ?-arrestin 2 activity in the forebrain. Neurobiol Dis 92:124-36
Arnatt, Christopher Kent; Zhang, Yan (2014) Bivalent ligands targeting chemokine receptor dimerization: molecular design and functional studies. Curr Top Med Chem 14:1606-18
Yuan, Yunyun (2014) Natural product chemokine receptor antagonists: What mother nature has offered us? Curr Top Med Chem 14:1619-34
Arnatt, Christopher K; Zhang, Yan (2013) G Protein-Coupled Estrogen Receptor (GPER) Agonist Dual Binding Mode Analyses toward Understanding of its Activation Mechanism: A Comparative Homology Modeling Approach. Mol Inform 32:647-658
Yuan, Yunyun; Arnatt, Christopher K; El-Hage, Nazira et al. (2013) A Bivalent Ligand Targeting the Putative Mu Opioid Receptor and Chemokine Receptor CCR5 Heterodimers: Binding Affinity versus Functional Activities. Medchemcomm 4:847-851
El-Hage, Nazira; Dever, Seth M; Podhaizer, Elizabeth M et al. (2013) A novel bivalent HIV-1 entry inhibitor reveals fundamental differences in CCR5-?-opioid receptor interactions between human astroglia and microglia. AIDS 27:2181-90
Yuan, Yunyun; Arnatt, Christopher K; Li, Guo et al. (2012) Design and synthesis of a bivalent ligand to explore the putative heterodimerization of the mu opioid receptor and the chemokine receptor CCR5. Org Biomol Chem 10:2633-46