Bivalent Ligand Aiming Putative Mu Opioid Receptor and Chemokine Receptor CXCR4 Dimers in Opioid Enhanced HIV-1 Entry

Abstract

A bivalent compound 1a featuring both a mu opioid receptor (MOR) and a CXCR4 antagonist pharmacophore (naltrexone and IT1t) was designed and synthesized. Further binding and functional studies demonstrated 1a acting as a MOR and a CXCR4 dual antagonist with reasonable binding affinities at both receptors. Furthermore, compound 1a seemed more effective than a combination of IT1t and naltrexone in inhibiting HIV entry at the presence of morphine. Additional molecular modeling results suggested that 1a may bind with the putative MOR-CXCR4 heterodimer to induce its anti-HIV activity. Collectively, bivalent ligand 1a may serve as a promising lead to develop chemical probes targeting the putative MOR-CXCR4 heterodimer in comprehending opioid exacerbated HIV-1 invasion.

Structure-Based Design and Development of Chemical Probes Targeting Putative MOR-CCR5 Heterodimers to Inhibit Opioid Exacerbated HIV-1 Infectivity

“…To further characterize the capacity of VZMC013 to block HIV-1 entry by occupying the HIV binding site on the CCR5, we utilized a well-established HIV-1 entry assay, in which the ability for small molecules to inhibit HIV-1 entry is measured as a decrease in HIV-1 reverse transcriptase (RT) activity that is equal to a decrease in radioactivity output after standard radioactive incorporation of tritiated thymidine triphosphate (needed for the synthesis of viral DNA). 62 This assay was run in GHOST-CCR5 cells using the CCR5-tropic viral strain HIV-1 BaL . Compounds VZMC001, VZMC002, VZMC013, and VZMC014 (maraviroc tested as the control) were subjected to this assay.…”

Beyond the Syndemic of Opioid Use Disorders and HIV: The Impact of Opioids on Viral Reservoirs

“…Several studies have reported that specific opioids could enhance HIV infectivity and replication through the upregulation of HIV co-receptors and impairment of intracellular innate antiviral responses [ 11 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. These findings may explain in vivo observations of a higher frequency of HIV founder viruses following intravenous opioid exposure and greater CD4 T-cell loss and viral set-point in macaques infected with the simian immunodeficiency virus (SIV) and undergoing long-term morphine administration [ 11 ].…”

“…Morphine, fentanyl, buprenorphine, and methadone may variably enhance CCR5 and CXCR4 expression in different cell types [ 11 , 32 , 33 , 36 , 37 ]. Methadone might even downregulate the natural chemokine competing for CCR5 (MIP-1b) in macrophages [ 34 ].…”

“…Since opioid receptors and CCR5/CXCR4 can undergo cross-talk with dimerization, approaches to inhibit HIV entry through bivalent compounds able to simultaneously interact with both receptors have proved promising [ 36 ]. For instance, a selective κ-opioid receptor (KOR) ligand inhibiting HIV expression in acutely infected human monocyte-derived macrophages [ 37 ], and a bivalent compound against μ-opioid receptor (MOR)-CCR5 heterodimer significantly reduced p24 levels in peripheral blood mononuclear cells (PBMCs), macrophages, and astrocytes [ 42 ].…”

Drugs of Abuse and Their Impact on Viral Pathogenesis

“…Exposure to the bivalent ligand significantly reduced HIV p24 levels in PBMCs, macrophages, and primary astrocytes. This group subsequently developed a bivalent MOR-CXCR4 antagonist that is around 150 times more potent than monovalent controls at inhibiting HIV entry [82], and have recently reported additional bivalent MOR-CCR5 ligands with potent anti-HIV activity [83].…”