title: 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.
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Arnatt
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA.
authors.forename: Bethany A
authors.initials: BA
authors.lastname: Falls
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.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Raborg
authors.affiliation: Department of Anatomy & Neurobiology, Virginia Commonwealth University, 1217 East Marshall Street, Richmond, VA 23298, USA.
authors.forename: Ruturaj R
authors.initials: RR
authors.lastname: Masvekar
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Richmond, VA 23298, USA.
authors.forename: Nazira
authors.initials: N
authors.lastname: El-Hage
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Richmond, VA 23298, USA.
authors.forename: Dana E
authors.initials: DE
authors.lastname: Selley
authors.affiliation: Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164, USA.
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Nicola
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Richmond, VA 23298, USA; Department of Anatomy & Neurobiology, Virginia Commonwealth University, 1217 East Marshall Street, Richmond, VA 23298, USA.
authors.forename: Pamela E
authors.initials: PE
authors.lastname: Knapp
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Richmond, VA 23298, USA; Department of Anatomy & Neurobiology, Virginia Commonwealth University, 1217 East Marshall Street, Richmond, VA 23298, USA.
authors.forename: Kurt F
authors.initials: KF
authors.lastname: Hauser
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA. Electronic address: yzhang2@vcu.edu.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003510:Cyclohexanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008024:Ligands; D000077592:Maraviroc; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009271:Naltrexone / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; C584933:CCR5 protein, human; D003510:Cyclohexanes; D008024:Ligands; D019713:Receptors, CCR5; D017450:Receptors, Opioid, mu; D014230:Triazoles; D009271:Naltrexone; D000077592:Maraviroc
keywords: Bivalent ligands; GPCR dimerization; NeuroAIDS; Structure–activity relationship