RESUMO
The first step for the HIV-1 virus infecting host cell is bound with the CCR5 chemokine receptor. A set of allosteric inhibitors of oximino-piperidino-piperidine antagonists for CCR5 chemokine receptor was discovered. However, the allosteric mechanism of these inhibitors is still unsolved. Therefore, residue-level dynamics correlation network combining with on molecular dynamics simulation was used to investigate the allosteric mechanism. The dynamics correlation network of bound CCR5 is significantly different from that of free CCR5. The community of the most active complex suggests that the allosteric information can freely transfer from the allosteric site to the effector site of the second extracellular loop, while the information transfers bottleneck for the less active one. Here, a hypothesis was proposed that "binding-induced allosteric mechanism" was used to reveal the allosteric regulation of antagonists and the network perturbation confirmed it. Finally, the shortest path algorithm was used to identify the possible allosteric pathway with Gly173-Lys171-Thr177-Tyr89-LIG which was evaluated by the network perturbation of key residue. Furthermore, the efficiency of allostery for the most active system is the highest among these antagonist complexes. The strategy targeting the allosteric pathway can be used to design novel inhibitors of HIV-1 virus.
Assuntos
Fármacos Anti-HIV/química , Antagonistas dos Receptores CCR5/química , Oximas/química , Piperidinas/química , Receptores CCR5/metabolismo , Sítio Alostérico , Sequência de Aminoácidos , Fármacos Anti-HIV/metabolismo , Antagonistas dos Receptores CCR5/metabolismo , Bases de Dados de Proteínas , Desenho de Fármacos , Infecções por HIV/metabolismo , Humanos , Simulação de Dinâmica Molecular , Conformação ProteicaRESUMO
C-C chemokine receptor 5(CCR5) is a cell membrane protein from G protein-coupled receptors (GPCR) family, which is an important modulator for leukocyte activation and mobilization. In the 1980s, several reports suggest that lack of the HIV-1 co-receptor, the chemokine receptor CCR5, offers protection against HIV infection. Later, it was shown that CCR5 was confirmed to be the most common co-receptor for the HIV-1 virus R5 strain. In recent years, many studies have shown that CCR5 is closely related to the development of various cancers and inflammations to facilitate the discovery of CCR5 antagonists. There are many types of CCR5 antagonists, mainly including chemokine derivatives, non-peptide small molecule compounds, monoclonal antibodies, and peptide compounds. This review focus on the recent research processes and pharmacological effects of CCR5 antagonists such as Maraviroc, TAK-779 and PRO 140. After focusing on the therapeutic effect of CCR5 antagonists on AIDS, it also discusses the therapeutic prospect of CCR5 in other diseases such as inflammation and tumor.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/uso terapêutico , Antagonistas dos Receptores CCR5/uso terapêutico , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Animais , Fármacos Anti-HIV/metabolismo , Anti-Inflamatórios/metabolismo , Antineoplásicos/metabolismo , Antagonistas dos Receptores CCR5/metabolismo , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Humanos , Inflamação/tratamento farmacológico , Neoplasias/tratamento farmacológico , Receptores CCR5/metabolismoRESUMO
BACKGROUND AND AIM: The hepatitis C virus (HCV) is a single-strand RNA virus that infects millions of people worldwide. Recent advances in therapy have led to viral cure using two- and three- drug combinations of direct acting inhibitors of viral replication. CCR5 is a chemokine receptor that is expressed on hepatocytes and represents a key co-receptor for HIV. We evaluated the effect of CCR5 blockade or knockdown on HCV replication in Huh7.5JFH1 cells. METHODS: Cells were exposed to varying concentrations of maraviroc (CCR5 inhibitor), cenicriviroc (CCR2/CCR5 inhibitor), sofosbuvir (nucleotide polymerase inhibitor), or raltegravir (HIV integrase inhibitor). RESULTS: HCV RNA was detected utilizing two qualitative strand-specific RT-PCR assays. HCV core antigen and NS3 protein was quantified in the supernatant and cell lysate, respectively. siRNA was utilized to knockdown CCR5 gene expression in hepatocytes. Alternatively, anti-CCR5 antibodies were employed to block the receptor. Supernatant levels of HCV RNA (expressed as fold change) were not reduced in the presence of raltegravir but were reduced 8.55-fold and 12.42-fold with cenicriviroc and maraviroc, respectively. Sofosbuvir resulted in a 16.20-fold change in HCV RNA levels. HCV core and NS3 protein production was also reduced in a dose-dependent manner. Two distinct anti-CCR5 antibodies also resulted in a significant reduction in HCV protein expression, as did siRNA knockdown of CCR5 gene expression. CONCLUSIONS: These data provide evidence that CCR5 modulation could have a significant effect on HCV replication in an in vitro system. Further evaluation of the role of CCR5 inhibition in clinical settings may be warranted.
Assuntos
Antagonistas dos Receptores CCR5/metabolismo , Hepacivirus/metabolismo , Replicação Viral/efeitos dos fármacos , Linhagem Celular , Hepacivirus/genética , Hepacivirus/patogenicidade , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Hepatócitos , Humanos , Imidazóis/uso terapêutico , Maraviroc/uso terapêutico , Raltegravir Potássico/uso terapêutico , Receptores CCR5/metabolismo , Sofosbuvir/uso terapêutico , SulfóxidosRESUMO
Marine micro-organisms have been proven to be excellent sources of bioactive compounds against HIV-1. Several natural products obtained from marine-derived Aspergillus fungi were screened for their activities to inhibit HIV-1 infection. Penicillixanthone A (PXA), a natural xanthone dimer from jellyfish-derived fungus Aspergillus fumigates, displayed potent anti-HIV-1 activity by inhibiting infection against CCR5-tropic HIV-1 SF162 and CXCR4-tropic HIV-1 NL4-3, with IC50 of 0.36 and 0.26 µM, respectively. Molecular docking study was conducted to understand the possible binding mode of PXA with the CCR5/CXCR4. The results revealed that, the marine-derived PXA, as a CCR5/CXCR4 dual-coreceptor antagonist, presents a new type of potential lead product for the development of anti-HIV therapeutics.
Assuntos
Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5/farmacologia , Receptores CCR5/metabolismo , Xantonas/farmacologia , Fármacos Anti-HIV/química , Organismos Aquáticos/química , Aspergillus/química , Antagonistas dos Receptores CCR5/química , Antagonistas dos Receptores CCR5/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Células HEK293 , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/patogenicidade , Humanos , Simulação de Acoplamento Molecular , Receptores CCR5/química , Receptores CXCR4/antagonistas & inibidores , Xantonas/química , Xantonas/metabolismoRESUMO
Principal component analysis (PCA), as a well-known multivariate data analysis and data reduction technique, is an important and useful algebraic tool in drug design and discovery. PCA, in a typical quantitative structure-activity relationship (QSAR) study, analyzes an original data matrix in which molecules are described by several intercorrelated quantitative dependent variables (molecular descriptors). Although extensively applied, there is disparity in the literature with respect to the applications of PCA in the QSAR studies. This study investigates the different applications of PCA in QSAR studies using a dataset including CCR5 inhibitors. The different types of preprocessing are used to compare the PCA performances. The use of PC plots in the exploratory investigation of matrix of descriptors is described. This work is also proved PCA analysis to be a powerful technique for exploring complex datasets in QSAR studies for identification of outliers. This study shows that PCA is able to easily apply to the pool of calculated structural descriptors and also the extracted information can be used to help decide upon an appropriate harder model for further analysis.
Assuntos
Antagonistas dos Receptores CCR5/química , Relação Quantitativa Estrutura-Atividade , Receptores CCR5/química , Algoritmos , Antagonistas dos Receptores CCR5/metabolismo , Desenho de Fármacos , Humanos , Análise de Componente Principal , Receptores CCR5/metabolismoRESUMO
Biophysical methods and x-ray crystallography have revealed that class A G protein-coupled receptors (GPCRs) can form homodimers. We combined computational approaches with receptor cross-linking, energy transfer, and a newly developed functional export assay to characterize the residues involved in the dimerization interfaces of the chemokine receptor CCR5, the major co-receptor for HIV-1 entry into cells. We provide evidence of three distinct CCR5 dimeric organizations, involving residues of transmembrane helix 5. Two dimeric states corresponded to unliganded receptors, whereas the binding of the inverse agonist maraviroc stabilized a third state. We found that CCR5 dimerization was required for targeting the receptor to the plasma membrane. These data suggest that dimerization contributes to the conformational diversity of inactive class A GPCRs and may provide new opportunities to investigate the cellular entry of HIV-1 and mechanisms for its inhibition.