Chemical Probes on NeuroAIDS

药物滥用直接导致美国三分之一的HIV-1感染。虽然流行病学数据已经证明阿片类药物滥用是HIV-1感染和进展为AIDS的危险因素，但越来越多的证据揭示了μ阿片类药物（莫尔）和CCR 5趋化因子受体在该病理过程中可能的协同相互作用。因此，深入了解可能参与阿片类药物增强HIV-1感染的神经通路至关重要。我们的假设是，含有莫尔拮抗剂和CCR 5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CCR 5的寡聚化独特地影响免疫细胞功能，并且它们的分子相互作用可能是它们在CNS中的明显协同作用的基础。二价配体已被证明是用于表征G蛋白偶联受体（GPCR）蛋白-蛋白相互作用、干扰与这些相互作用相关的正常功能或甚至通过靶向这些相互作用来治疗疾病的强大分子工具。我们相信这种配体不仅可以作为一种药理学探针，以帮助澄清阿片类药物滥用增强HIV-1感染的机制，并了解由于药物滥用和HIV-1感染引起的痴呆的神经发病机制，而且还可以治疗抑制这种增强的HIV-1感染。因此，本项目的长期目标是利用此类二价配体阐明阿片类药物增强HIV-1感染的分子机制，并探索这些配体在阿片类药物滥用和HIV-1感染相关痴呆治疗中的潜在应用。该建议的具体目标是：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检测二价配体; 2）检测二价配体通过CCR 5和MOR-CCR 5相互作用阻断HIV-1进入和感染性的功效;和3）通过应用二价配体探针研究neuroAIDS的发病机制。

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.