RESUMO
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.
Assuntos
Fármacos Anti-HIV/farmacologia , Cicloexanos/farmacologia , Infecções por HIV/tratamento farmacológico , Naltrexona/farmacologia , Receptores CCR5/metabolismo , Receptores Opioides mu/antagonistas & inibidores , Triazóis/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Cicloexanos/síntese química , Cicloexanos/química , Dimerização , Relação Dose-Resposta a Droga , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Ligantes , Maraviroc , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Naltrexona/síntese química , Naltrexona/química , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/químicaRESUMO
Prostate cancer is one of the leading causes of death among males in the world. Prostate cancer cells have been shown to express upregulated chemokine receptor CCR5, a G protein-coupled receptor (GPCR) that relates to the inflammation process. Anibamine, a natural product containing a pyridine ring and two aliphatic side chains, was shown to carry a binding affinity of 1 µM at CCR5 as an antagonist with potential anti-cancer activity. However, it is not drug-like according to the Lipinski's rule of five mainly due to its two long aliphatic side chains. In our effort to improve its drug-like property, a series of anibamine derivatives were designed and synthesized by placement of aromatic side chains through an amide linkage to the pyridine ring. The newly synthesized compounds were tested for their CCR5 affinity and antagonism, and potential anti-proliferation activity against prostate cancer cell lines. Basal cytotoxicity was finally studied for compounds showing potent anti-proliferation activity. It was found that compounds with hydrophobic substitutions on the aromatic systems seemed to carry more promising CCR5 binding and prostate cancer cell proliferation inhibition activities.