Exploration of bivalent ligands targeting putative mu opioid receptor and chemokine receptor CCR5 dimerization.
Bioorg Med Chem
; 24(22): 5969-5987, 2016 11 15.
Article
em En
| MEDLINE
| ID: mdl-27720326
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.
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MEDLINE
Assunto principal:
Triazóis
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Infecções por HIV
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Receptores Opioides mu
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Fármacos Anti-HIV
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Receptores CCR5
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Cicloexanos
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Naltrexona
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article