Exploration of bivalent ligands targeting putative mu opioid receptor and chemokine receptor CCR5 dimerization

Abstract

Modern antiretroviral therapies have provided HIV-1 infected patients longer lifespans and better quality of life. However, several neurological complications are now being seen in these patients due to HIV-1 associated injury of neurons by infected microglia and astrocytes. In addition, these effects can be further exacerbated with opiate use and abuse. One possible mechanism for such potentiation effects of opiates is the interaction of the mu opioid receptor (MOR) with the chemokine receptor CCR5 (CCR5), a known HIV-1 co-receptor, to form MOR-CCR5 heterodimer. In an attempt to understand this putative interaction and its relevance to neuroAIDS, we designed and synthesized a series of bivalent ligands targeting the putative CCR5-MOR heterodimer. To understand how these bivalent ligands may interact with the heterodimer, biological studies including calcium mobilization inhibition, binding affinity, HIV-1 invasion, and cell fusion assays were applied. In particular, HIV-1 infection assays using human peripheral blood mononuclear cells, macrophages, and astrocytes revealed a notable synergy in activity for one particular bivalent ligand. Further, a molecular model of the putative CCR5-MOR heterodimer was constructed, docked with the bivalent ligand, and molecular dynamics simulations of the complex was performed in a membrane-water system to help understand the biological observation.

The blockade of CC chemokine receptor type 1 influences the level of nociceptive factors and enhances opioid analgesic potency in a rat model of neuropathic pain

“…The other explanation for better opioid efficacy might be the formation of heterodimers between chemokine receptors and opioid receptors (e.g. CCR5‐MOR, CXCR2‐DOR, CXCR4‐DOR) . To our knowledge, there is still no evidence that CCR1 creates dimers with opioid receptors.…”

“…CCR5-MOR, CXCR2-DOR, CXCR4-DOR). [99][100][101] To our knowledge, there is still no evidence that CCR1 creates dimers with opioid receptors. However, further studies are needed because it is known that CCR1 is able to heterodimerize with other chemokine receptors (e.g.…”

A central role for glial CCR5 in directing the neuropathological interactions of HIV-1 Tat and opiates

“…Heterologous desensitization may explain a reduced chemotactic effect of CCR5 by pretreatment with MOR agonists [ 80 ]. Recently, synthetic, bivalent ligands composed of maraviroc and naltrexone that target the proposed CCR5-MOR heteromers/oligomers have shown that such interactions may occur in a cell type-specific manner [ 84 – 86 ]. The inability to form MOR-CCR5 heterodimers in CCR5-null (or MOR-null) glia may alter the cellular response to concurrent morphine exposure, contributing to neuroprotection.…”

Design and synthesis of a bivalent probe targeting the putative mu opioid receptor and chemokine receptor CXCR4 heterodimer

“…[52][53][54] Based on previous bivalent ligand series reported from the literature, the attachment locus on naltrexone was chosen to be the C6-position after transforming the carbonyl group to the 6β-amino group. 44,45,[55][56][57][58][59] The attachment locus on IT1t was identified based on the available CXCR4-IT1t co-crystal structure (PDB: 3ODU). 30 In the binding cavity it was observed that the cyclohexyl groups adjacent to the symmetric isothiourea moiety of IT1t were pointing upward and away from the TM bundle and toward the extracellular space.…”