Chemical Probes on NeuroAIDS

在美国，药物滥用直接导致了三分之一的HIV-1感染。虽然流行病学数据表明阿片类药物滥用是HIV-1感染和发展为艾滋病的危险因素，但越来越多的证据表明，在这一病理过程中，mu阿片类药物（MOR）和CCR5趋化因子受体之间可能存在协同作用。因此，彻底了解可能参与阿片类药物增强HIV-1感染的神经通路是必不可少的。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表征g蛋白偶联受体（GPCR）蛋白-蛋白相互作用的强大分子工具，可以干扰与这些相互作用相关的正常功能，甚至可以通过靶向这些相互作用来治疗疾病。我们相信这种配体不仅可以作为一种药理学探针，帮助阐明阿片类药物滥用增强HIV-1感染的机制，并了解药物滥用和HIV-1感染引起的痴呆的神经发病机制，而且还可以抑制这种增强的HIV-1感染。因此，本项目的长期目标是利用这种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感染相关痴呆方面的潜在应用。本提案的具体目的是：1)表征二价

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.