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1.
Neurotherapeutics ; 17(3): 1170-1183, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31898284

RESUMO

The activation of C-C chemokine receptor type 1 (CCR1) has been shown to be pro-inflammatory in several animal models of neurological diseases. The objective of this study was to investigate the activation of CCR1 on neuroinflammation in a mouse model of intracerebral hemorrhage (ICH) and the mechanism of CCR1/tetratricopeptide repeat 1 (TPR1)/extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway in CCR1-mediated neuroinflammation. Adult male CD1 mice (n = 210) were used in the study. The selective CCR1 antagonist Met-RANTES was administered intranasally at 1 h after autologous blood injection. To elucidate potential mechanism, a specific ERK1/2 activator (ceramide C6) was administered prior to Met-RANTES treatment; CCR1 activator (recombinant CCL5, rCCL5) and TPR1 CRISPR were administered in naïve mouse. Neurobehavioral assessments, brain water content, immunofluorescence staining, and western blot were performed. The endogenous expressions of CCR1, CCL5, TPR1, and p-ERK1/2 were increased in the brain after ICH. CCR1 were expressed on microglia, neurons, and astrocytes. The inhibition of CCR1 with Met-RANTES improved neurologic function, decreased brain edema, and suppressed microglia/macrophage activations and neutrophil infiltration after ICH. Met-RANTES treatment decreased expressions of CCR1, TPR1, p-ERK, TNF-α, and IL-1ß, which was reversed by ceramide C6. The brain CCR1 activation by rCCL5 injection in naïve mouse resulted in neurological deficits and increased expressions of CCR1, TPR1, p-ERK, TNF-α, and IL-1ß. These detrimental effects of rCCL5 were reversed by TPR1 knockdown using TPR1 CRISPR. Our study demonstrated that CCR1 activation promoted neuroinflammation through CCR1/TPR1/ERK1/2 signaling pathway after ICH in mice. CCR1 inhibition with Met-RANTES attenuated neuroinflammation, thereby reducing brain edema and improving neurobehavioral functions. Targeting CCR1 activation may provide a promising therapeutic approach in the management of ICH patients.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Hemorragia Cerebral/metabolismo , Proteínas Heterotriméricas de Ligação ao GTP/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Receptores CCR1/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/patologia , Quimiocina CCL5/farmacologia , Quimiocina CCL5/uso terapêutico , Inflamação/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Receptores CCR1/agonistas , Receptores CCR1/antagonistas & inibidores
2.
Int J Mol Sci ; 20(10)2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096719

RESUMO

Leukocyte migration, a hallmark of the inflammatory response, is stimulated by the interactions between chemokines, which are expressed in injured or infected tissues, and chemokine receptors, which are G protein-coupled receptors (GPCRs) expressed in the leukocyte plasma membrane. One mechanism for the regulation of chemokine receptor signaling is biased agonism, the ability of different chemokine ligands to preferentially activate different intracellular signaling pathways via the same receptor. To identify features of chemokines that give rise to biased agonism, we studied the activation of the receptor CCR1 by the chemokines CCL7, CCL8, and CCL15(Δ26). We found that, compared to CCL15(Δ26), CCL7 and CCL8 exhibited biased agonism towards cAMP inhibition and away from ß-Arrestin 2 recruitment. Moreover, N-terminal substitution of the CCL15(Δ26) N-terminus with that of CCL7 resulted in a chimera with similar biased agonism to CCL7. Similarly, N-terminal truncation of CCL15(Δ26) also resulted in signaling bias between cAMP inhibition and ß-Arrestin 2 recruitment signals. These results show that the interactions of the chemokine N-terminal region with the receptor transmembrane region play a key role in selecting receptor conformations coupled to specific signaling pathways.


Assuntos
Quimiocinas/metabolismo , Quimiocinas/farmacologia , Receptores CCR1/agonistas , Receptores CCR1/metabolismo , Transdução de Sinais , Quimiocina CCL7/metabolismo , Quimiocina CCL8/metabolismo , Quimiocinas CC/metabolismo , Células HEK293 , Humanos , Ligantes , Proteínas Inflamatórias de Macrófagos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , beta-Arrestina 2/metabolismo
3.
Curr Top Med Chem ; 14(13): 1553-73, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25159162

RESUMO

While a number of agents directed at chemokine receptors have entered clinic trials, the vast majority of these have failed, and the enthusiasm for this class of drugs has been attenuated. To date, there are two drugs that inhibit chemokine receptors approved by the FDA. The first to be approved in 2007 was maraviroc (brand name Selzentry, or Celsentri outside the US) which targets CCR5 and is used for the treatment of HIV infection. The second is plerixafor (Mozobil) which was approved in 2008, targets CXCR4, and is used for the mobilization of hematopoietic stem cells. This review will focus on the CC chemokine receptors CCR1 and CCR5. These G protein coupled receptors are both activated by a relatively large number of chemokines, most of which overlap. While most of the drugs for CCR1 have been assessed in the context of autoimmune diseases like multiple sclerosis and rheumatoid arthritis, and those for CCR5 were examined for HIV-infection, we review the role of these receptors in relation to cancer. Recently introduced pharmacophores that serve as agonists or antagonists for the receptors are presented. Efforts to exploit polypharmacology approaches using promiscuous compounds that target more than one receptor are also considered.


Assuntos
Antineoplásicos/farmacologia , Cicloexanos/farmacologia , Neoplasias/tratamento farmacológico , Receptores CCR1/agonistas , Receptores CCR1/antagonistas & inibidores , Receptores CCR5/agonistas , Triazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Cicloexanos/química , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Humanos , Maraviroc , Estrutura Molecular , Neoplasias/metabolismo , Receptores CCR1/metabolismo , Receptores CCR5/metabolismo , Triazóis/química
4.
J Chem Inf Model ; 53(11): 2863-73, 2013 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-24083637

RESUMO

Chemokine receptors are involved in trafficking of leukocytes and represent targets for autoimmune conditions, inflammatory diseases, viral infections, and cancer. We recently published CCR1, CCR8, and CCR5 agonists and positive modulators based on a three metal-ion chelator series: 2,2'-bipyridine, 1,10-phenanthroline, and 2,2';6',2″-terpyridine. Here, we have performed an in-depth structure-activity relationship study and tested eight new optimized analogs. Using density functional theory calculations we demonstrate that the chelator zinc affinities depend on how electron-donating and -withdrawing substituents modulate the partial charges of chelating nitrogens. The zinc affinity was found to constitute the major factor for receptor potency, although the activity of some chelators deviate suggesting favorable or unfavorable interactions. Hydrophobic and halogen substituents are generally better accommodated in the receptors than polar groups. The new analog brominated terpyridine (29) resulted in the highest chelator potencies observed so far CCR1 (EC50: 0.49 µM) and CCR8 (EC50: 0.28 µM). Furthermore, we identified the first selective CCR5 agonist chelator, meta dithiomethylated bipyridine (23). The structure-activity relationships contribute to small-molecule drug development, and the novel chelators constitute valuable tools for studies of structural mechanisms for chemokine receptor activation.


Assuntos
2,2'-Dipiridil/análogos & derivados , Quelantes/química , Fenantrolinas/química , Piridinas/química , Receptores CCR1/química , Receptores CCR5/química , Receptores CCR8/química , Zinco/química , 2,2'-Dipiridil/química , Animais , Antagonistas dos Receptores CCR5 , Células COS , Chlorocebus aethiops , Expressão Gênica , Halogenação , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Receptores CCR1/agonistas , Receptores CCR1/antagonistas & inibidores , Receptores CCR1/genética , Receptores CCR5/agonistas , Receptores CCR5/genética , Receptores CCR8/agonistas , Receptores CCR8/antagonistas & inibidores , Receptores CCR8/genética , Relação Estrutura-Atividade
5.
Mol Pharmacol ; 84(3): 335-45, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23765404

RESUMO

In addition to the 7 transmembrane receptor (7TM)-conserved disulfide bridge between transmembrane (TM) helix 3 and extracellular loop (ECL)-2, chemokine receptors (CCR) contain a disulfide bridge between the N terminus and what previously was believed to be ECL-3. Recent crystal and NMR structures of the CXC chemokine receptors (CXCR) CXCR4 and CXCR1, combined with structural analysis of all endogenous chemokine receptors indicate that this chemokine receptor-conserved bridge in fact connects the N terminus to the top of TM-7. By employing chemokine ligands that mainly target extracellular receptor regions and small-molecule ligands that predominantly interact with residues in the main binding crevice, we show that the 7TM-conserved bridge is essential for all types of ligand-mediated activation, whereas the chemokine-conserved bridge is dispensable for small-molecule activation in CCR1. However, in striking contrast to previous studies in other chemokine receptors, high-affinity CCL3 chemokine binding was maintained in the absence of either bridge. In the highly related CCR5, a completely different dependency was observed as neither activation nor binding of the same chemokines was retained in the absence of either bridge. In contrast, both bridges were dispensable for activation by the same small molecules. This indicates that CCR5 activity is independent of extracellular regions, whereas in CCR1 the preserved folding of ECL-2 is necessary for activation. These results indicate that conserved structural features in a receptor subgroup do not necessarily provide specific traits for the whole subgroup but rather provide unique traits to the single receptors.


Assuntos
Dissulfetos/metabolismo , Receptores CCR1/metabolismo , Receptores CCR5/metabolismo , Regulação Alostérica , Animais , Arrestinas/metabolismo , Ligação Competitiva , Antagonistas dos Receptores CCR5 , Células COS , Quimiocina CCL1/farmacologia , Quimiocina CCL3/farmacologia , Quimiocina CCL5/farmacologia , Chlorocebus aethiops , Humanos , Ligantes , Mutagênese Sítio-Dirigida , Dobramento de Proteína , Receptores CCR1/agonistas , Receptores CCR1/antagonistas & inibidores , Receptores CCR5/agonistas , beta-Arrestinas
6.
J Immunol ; 189(11): 5266-76, 2012 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-23125416

RESUMO

Agonists of CCR1 contribute to hypersensitivity reactions and atherosclerotic lesions, possibly via the regulation of the transcription factor STAT3. CCR1 was demonstrated to use pertussis toxin-insensitive Gα(14/16) to stimulate phospholipase Cß and NF-κB, whereas both Gα(14) and Gα(16) are also capable of activating STAT3. The coexpression of CCR1 and Gα(14/16) in human THP-1 macrophage-like cells suggests that CCR1 may use Gα(14/16) to induce STAT3 activation. In this study, we demonstrated that a CCR1 agonist, leukotactin-1 (CCL15), could indeed stimulate STAT3 Tyr(705) and Ser(727) phosphorylation via pertussis toxin-insensitive G proteins in PMA-differentiated THP-1 cells, human erythroleukemia cells, and HEK293 cells overexpressing CCR1 and Gα(14/16). The STAT3 Tyr(705) and Ser(727) phosphorylations were independent of each other and temporally distinct. Subcellular fractionation and confocal microscopy illustrated that Tyr(705)-phosphorylated STAT3 translocated to the nucleus, whereas Ser(727)-phosphorylated STAT3 was retained in the cytosol after CCR1/Gα(14) activation. CCL15 was capable of inducing IL-6 and IL-8 (CXCL8) production in both THP-1 macrophage-like cells and HEK293 cells overexpressing CCR1 and Gα(14/16). Neutralizing Ab to IL-6 inhibited CCL15-mediated STAT3 Tyr(705) phosphorylation, whereas inhibition of STAT3 activity abolished CCL15-activated CXCL8 release. The ability of CCR1 to signal through Gα(14/16) provides a linkage for CCL15 to regulate IL-6/STAT3-signaling cascades, leading to expression of CXCL8, a cytokine that is involved in inflammation and the rupture of atherosclerotic plaque.


Assuntos
Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/imunologia , Interleucina-6/imunologia , Interleucina-8/imunologia , Macrófagos/imunologia , Receptores CCR1/imunologia , Fator de Transcrição STAT3/imunologia , Anticorpos/farmacologia , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/genética , Núcleo Celular/imunologia , Quimiocinas CC/imunologia , Quimiocinas CC/farmacologia , Citosol/efeitos dos fármacos , Citosol/imunologia , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Células HEK293 , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-8/biossíntese , Células K562 , Proteínas Inflamatórias de Macrófagos/imunologia , Proteínas Inflamatórias de Macrófagos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Toxina Pertussis/farmacologia , Fosforilação , Plasmídeos , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Receptores CCR1/agonistas , Receptores CCR1/genética , Fator de Transcrição STAT3/genética , Serina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transfecção , Tirosina/metabolismo
7.
Br J Pharmacol ; 166(1): 258-75, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22050085

RESUMO

BACKGROUND AND PURPOSE: The majority of small molecule compounds targeting chemokine receptors share a similar pharmacophore with a centrally located aliphatic positive charge and flanking aromatic moieties. Here we describe a novel piperidine-based compound with structural similarity to previously described CCR8-specific agonists, but containing a unique phenyl-tetrazol moiety which, in addition to activity at CCR8 was also active at CCR1. EXPERIMENTAL APPROACH: Single point mutations were introduced in CCR1 and CCR8, and their effect on small molecule ligand-induced receptor activation was examined through inositol trisphosphate (IP(3) ) accumulation. The molecular interaction profile of the agonist was verified by molecular modeling. KEY RESULTS: The chemokine receptor conserved glutamic acid in TM-VII served as a common anchor for the positively charged amine in the piperidine ring. However, whereas the phenyl-tetrazol group interacted with TyrIV:24 (Tyr(172) ) and TyrIII:09 (Tyr(114) ) in the major binding pocket (delimited by TM-III to VII) of CCR8, it also interacted with TrpII:20 (Trp(90) ) and LysII:24 (Lys(94) ) in the minor counterpart (delimited TM-I to III, plus TM-VII) in CCR1. A straightening of TM-II by Ala-substitution of ProII:18 confirmed its unique role in CCR1. The extracellular loop 2 (ECL-2) contributed directly to the small molecule binding site in CCR1, whereas it contributed to efficacy, but not potency in CCR8. CONCLUSION AND IMPLICATIONS: Despite high ligand potency and efficacy and receptor similarity, this dual-active and bitopic compound binds oppositely in CCR1 and CCR8 with different roles of ECL-2, thereby expanding and diversifying the influence of extracellular receptor regions in drug action.


Assuntos
Inositol 1,4,5-Trifosfato/metabolismo , Piperidinas/farmacologia , Receptores CCR1/metabolismo , Receptores CCR8/metabolismo , Tetrazóis/farmacologia , Animais , Sítios de Ligação , Células COS , Chlorocebus aethiops , Ácido Glutâmico/metabolismo , Humanos , Ligantes , Modelos Moleculares , Piperidinas/química , Piperidinas/metabolismo , Mutação Puntual , Receptores CCR1/agonistas , Receptores CCR1/genética , Receptores CCR8/agonistas , Receptores CCR8/genética , Tetrazóis/química , Tetrazóis/metabolismo
8.
Bioorg Med Chem Lett ; 22(1): 293-5, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-22104149

RESUMO

A bis-quinoline compound, (7-chloro-N-(4-(7-chloroquinolin-4-ylamino)butyl)quinolin-4-amine; RE-660) was found to have C-C chemokine receptor type 1 (CCR1)-agonistic properties. RE-660 displayed strong adjuvantic activity in mice when co-administered with bovine α-lactalbumin used as a model subunit protein antigen. RE-660 evoked a balanced Th1 (IgG2)/Th2 (IgG1) antibody profile, and the quality of antibodies elicited by the bis-quinoline was found to be superior to that evoked by glucopyranosyl lipid A by surface plasmon resonance experiments. No evidence of proinflammatory activity was observed in human blood ex vivo models. In preliminary acute toxicity studies, the compound was found to be of lower toxicity than chloroquine in mice, and was non-mutagenic in an Ames screen.


Assuntos
Quinolinas/farmacologia , Receptores CCR1/agonistas , Animais , Bovinos , Cloroquina/química , Relação Dose-Resposta a Droga , Humanos , Imunoglobulina G/metabolismo , Inflamação , Lactalbumina/química , Lipídeos/química , Camundongos , Modelos Químicos , Testes de Mutagenicidade , Quinolinas/síntese química , Relação Estrutura-Atividade , Ativação Transcricional
9.
Methods Enzymol ; 461: 171-90, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19480919

RESUMO

Chemokine receptors belong to the large family of 7-transmembrane (7TM) G-protein-coupled receptors. These receptors are targeted and activated by a variety of different ligands, indicating that activation is a result of similar molecular mechanisms but not necessarily similar modes of ligand binding. Attempts to unravel the activation mechanism of 7TM receptors have led to the conclusion that activation involves movements of the transmembrane segments VI and VII in particular, as recently gathered in the Global Toggle Switch Model. However, to understand the activation mechanism completely, more research has to be done in this field. Chemokine receptors are interesting tools in this matter. First, the chemokine system has a high degree of promiscuity that allows several chemokines to target one receptor in different ways, as well as a single chemokine ligand to target several receptors in different ways. Second, the endogenous ligands are large proteins that mainly activate their cognate receptors by interacting with various extracellular-located receptor regions. It is, however, also possible to introduce agonism of simple ligands like metal ions. Thus, the chemokine system offers the possibility to test and compare the activation profiles of several chemically diverse ligands. This also brings up the interesting discussion of allosterism, because small molecules in the chemokine field often interact with allosteric receptor sites.


Assuntos
Receptores de Quimiocinas/química , Receptores de Quimiocinas/metabolismo , Regulação Alostérica , Animais , Células COS , Chlorocebus aethiops , Humanos , Modelos Biológicos , Ligação Proteica/fisiologia , Conformação Proteica , Receptores CCR1/agonistas , Receptores CCR1/antagonistas & inibidores , Receptores CCR1/química , Receptores CCR1/metabolismo , Receptores CCR8/agonistas , Receptores CCR8/antagonistas & inibidores , Receptores CCR8/química , Receptores CCR8/metabolismo , Receptores CXCR3/agonistas , Receptores CXCR3/antagonistas & inibidores , Receptores CXCR3/química , Receptores CXCR3/metabolismo , Receptores de Quimiocinas/agonistas , Receptores de Quimiocinas/antagonistas & inibidores
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