title: A Bivalent Ligand Targeting the Putative Mu Opioid Receptor and Chemokine Receptor CCR5 Heterodimers: Binding Affinity versus Functional Activities.
abstract: Opioid substitution and antiretroviral therapies have steadily increased the life spans of AIDS patients with opioid addiction, while the adverse drug-drug interactions and persistence of HIV-associated neurocognitive disorders still require new strategies to target opioid abuse and HIV-1 comorbidities. A bivalent ligand1with a 21-atom spacer was thus synthesized and explicitly characterized as a novel pharmacological probe to study the underlying mechanism of opioid-enhanced NeuroAIDS. The steric hindrance generated from the spacer affected the binding affinity and Ca2+flux inhibition function activity of bivalent ligand1at the chemokine receptor CCR5 more profoundly than it did at the mu opioid receptor (MOR). However, the CCR5 radioligand binding affinity and the Ca2+flux inhibition function of the ligand seemed not necessarily to correlate with its antiviral activity given that it was at least two times more potent than maraviroc alone in reducing Tat expression upon HIV-1 infection in human astrocytes. Furthermore, the ligand was also about two times more potent than the simple mixture of maraviroc and naltrexone in the same viral entry inhibition assay. Therefore bivalent ligand1seemed to function more effectively by targeting specifically the putative MOR-CCR5 heterodimer in the viral invasion process. The results reported here suggest that a properly designed bivalent ligand may serve as a useful chemical probe to study the potential MOR-CCR5 interaction during the progression of NeuroAIDS.
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Yuan
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Arnatt
authors.forename: Nazira
authors.initials: N
authors.lastname: El-Hage
authors.forename: Seth M
authors.initials: SM
authors.lastname: Dever
authors.forename: Joanna C
authors.initials: JC
authors.lastname: Jacob
authors.forename: Dana E
authors.initials: DE
authors.lastname: Selley
authors.forename: Kurt F
authors.initials: KF
authors.lastname: Hauser
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
keywords: CCR5; MOR; NeuroAIDS; bivalent ligand; functional selectivity