RESUMO
Polyunsaturated fatty acids and their metabolites have been reported in which their pathway has potential for the modulation of cancer cell growth. 13-(S)-HODE and 15-(S)-HETE, both of which are main metabolites of 15-LOXs, play an important role as endogenous ligands in biological systems. However, the modification of 13-(S)-HODE and 15-(S)-HETE in pharmaceutical applications has not been explored widely. Herein, we report the stereoselective syntheses of 13-(S)-HODE, 15-(S)-HETE, and its derivatives to enable the synthesis of bioactive fatty acid analogues.
Assuntos
Ácidos Graxos Insaturados , Ácidos Hidroxieicosatetraenoicos , Estereoisomerismo , Ácidos Hidroxieicosatetraenoicos/química , Ácidos Hidroxieicosatetraenoicos/síntese química , Ácidos Graxos Insaturados/química , Ácidos Graxos Insaturados/síntese química , Estrutura Molecular , Ácidos Linoleicos/química , Ácidos Linoleicos/síntese químicaRESUMO
Sac embolization of abdominal aortic aneurysms (AAAs) remains clinically limited by endoleak recurrences. These recurrences are correlated with recanalization due to the presence of endothelial lining and matrix metalloproteinases (MMPs)-mediated aneurysm progression. This study incorporated doxycycline (DOX), a well-known sclerosant and MMPs inhibitor, into a shear-thinning biomaterial (STB)-based vascular embolizing hydrogel. The addition of DOX was expected to improve embolizing efficacy while preventing endoleaks by inhibiting MMP activity and promoting endothelial removal. The results showed that STBs containing 4.5% w/w silicate nanoplatelet and 0.3% w/v of DOX were injectable and had a 2-fold increase in storage modulus compared to those without DOX. STB-DOX hydrogels also reduced clotting time by 33% compared to untreated blood. The burst release of DOX from the hydrogels showed sclerosing effects after 6 h in an ex vivo pig aorta model. Sustained release of DOX from hydrogels on endothelial cells showed MMP inhibition (ca. an order of magnitude larger than control groups) after 7 days. The hydrogels successfully occluded a patient-derived abdominal aneurysm model at physiological blood pressures and flow rates. The sclerosing and MMP inhibition characteristics in the engineered multifunctional STB-DOX hydrogels may provide promising opportunities for the efficient embolization of aneurysms in blood vessels.
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Inositol polyphosphates (IPs) are a group of inositol metabolites that act as secondary messengers for external signalling cues. They play various physiological roles such as insulin release, telomere length maintenance, cell metabolism, and aging. Inositol hexakisphosphate kinase 2 (IP6K2) is a key enzyme that produces 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5-IP7), which influences the early stages of glucose-induced exocytosis. Therefore, regulation of IP6Ks may serve as a promising strategy for treating diseases such as diabetes and obesity. In this study, we designed, synthesised, and evaluated flavonoid-based compounds as new inhibitors of IP6K2. Structure-activity relationship studies identified compound 20s as the most potent IP6K2 inhibitor with an IC50 value of 0.55 µM, making it 5-fold more potent than quercetin, the reported flavonoid-based IP6K2 inhibitor. Compound 20s showed higher inhibitory potency against IP6K2 than IP6K1 and IP6K3. Compound 20s can be utilised as a hit compound for further structural modifications of IP6K2 inhibitors.
Assuntos
Inibidores Enzimáticos , Flavonoides , Insulina , Fosfotransferases (Aceptor do Grupo Fosfato) , Flavonoides/farmacologia , Inositol , Transdução de Sinais , Fosfotransferases (Aceptor do Grupo Fosfato)/antagonistas & inibidores , Inibidores Enzimáticos/farmacologiaRESUMO
PURPOSE: Radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) is emerging as an effective treatment option for metastatic castration-resistant prostate cancer (mCRPC). An imaging-based method to quantify early treatment responses can help to understand and optimize RLT. METHODS: We developed a self-triggered probe 2 targeting the colocalization of PSMA and caspase-3 for fluorescence imaging of RLT-induced apoptosis. RESULTS: The probe binds to PSMA potently with a Ki of 4.12 nM, and its fluorescence can be effectively switched on by caspase-3 with a Km of 67.62 µM. Cellular and in vivo studies demonstrated its specificity for imaging radiation-induced caspase-3 upregulation in prostate cancer. To identify the detection limit of our method, we showed that probe 2 could achieve 1.79 times fluorescence enhancement in response to 177Lu-RLT in a medium PSMA-expressing 22Rv1 xenograft model. CONCLUSION: Probe 2 can potently bind to PSMA, and the fluorescence signal can be sensitively switched on by caspase-3 both in vitro and in vivo. This method may provide an effective tool to investigate and optimize PSMA-RLT.
Assuntos
Lutécio , Neoplasias de Próstata Resistentes à Castração , Antígenos de Superfície , Caspase 3 , Dipeptídeos , Glutamato Carboxipeptidase II , Compostos Heterocíclicos com 1 Anel , Humanos , Lutécio/uso terapêutico , Masculino , Imagem Óptica , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/radioterapia , Resultado do TratamentoRESUMO
Inositol hexakisphosphate kinase (IP6K) is an important mammalian enzyme involved in various biological processes such as insulin signalling and blood clotting. Recent analyses on drug metabolism and pharmacokinetic properties on TNP (N2-(m-trifluorobenzyl), N6-(p-nitrobenzyl)purine), a pan-IP6K inhibitor, have suggested that it may inhibit cytochrome P450 (CYP450) enzymes and induce unwanted drug-drug interactions in the liver. In this study, we confirmed that TNP inhibits CYP3A4 in type I binding mode more selectively than the other CYP450 isoforms. In an effort to find novel purine-based IP6K inhibitors with minimal CYP3A4 inhibition, we designed and synthesised 15 TNP analogs. Structure-activity relationship and biochemical studies, including ADP-Glo kinase assay and quantification of cell-based IP7 production, showed that compound 9 dramatically reduced CYP3A4 inhibition while retaining IP6K-inhibitory activity. Compound 9 can be a tool molecule for structural optimisation of purine-based IP6K inhibitors.
Assuntos
Citocromo P-450 CYP3A/metabolismo , Inibidores Enzimáticos/farmacologia , Fosfotransferases (Aceptor do Grupo Fosfato)/antagonistas & inibidores , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Fosfotransferases (Aceptor do Grupo Fosfato)/metabolismo , Relação Estrutura-AtividadeRESUMO
Bacterial biofilm formation causes serious problems in various fields of medical, clinical, and industrial settings. Antibiotics and biocide treatments are typical methods used to remove bacterial biofilms, but biofilms are difficult to remove effectively from surfaces due to their increased resistance. An alternative approach to treatment with antimicrobial agents is using biofilm inhibitors that regulate biofilm development without inhibiting bacterial growth. In the present study, we found that linoleic acid (LA), a plant unsaturated fatty acid, inhibits biofilm formation under static and continuous conditions without inhibiting the growth of Pseudomonas aeruginosa. LA also influenced the bacterial motility, extracellular polymeric substance production, and biofilm dispersion by decreasing the intracellular cyclic diguanylate concentration through increased phosphodiesterase activity. Furthermore, quantitative gene expression analysis demonstrated that LA induced the expression of genes associated with diffusible signaling factor-mediated quorum sensing that can inhibit or induce the dispersion of P. aeruginosa biofilms. These results suggest that LA is functionally and structurally similar to a P. aeruginosa diffusible signaling factor (cis-2-decenoic acid) and, in turn, act as an agonist molecule in biofilm dispersion.
Assuntos
Biofilmes/efeitos dos fármacos , Ácidos Graxos Monoinsaturados/metabolismo , Ácido Linoleico/farmacologia , Pseudomonas aeruginosa/fisiologia , Percepção de Quorum/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimentoRESUMO
The abnormal self-assembly of amyloid-beta (Aß) peptides into oligomers, as well as insoluble fibrils, has been identified as a key factor for monitoring the progression of Alzheimer's disease (AD). The noninvasive imaging of Aß aggregates utilizing chemical probes can be a powerful and practical technique for accurately diagnosing and monitoring the progress of AD, as well as evaluating the effectiveness of therapeutic drug candidates in treating or managing it. Particularly, the near-infrared (NIR) fluorescence imaging of Aß plaques is a potentially promising approach toward the efficient detection of the biomarker. In this study, we describe a new NIR fluorophore, which was based on curcumin derivatives. The fluorophore is equipped with desirable optical properties for in vivo brain imaging. The emission wavelength of the probe, 8b, is 667 nm, and its fluorescent intensity is significantly increased through binding with the Aß aggregates. The probe allows the clear visualization of the Aß plaques 10 min post administration, and the intensity of the fluorescent signal in the brain of a 5XFAD transgenic mouse model is more than three times higher than that of the normal control group. These results demonstrate that the designed probe can be an effective tool for visualizing Aß plaques, as well as investigating the pathological progress of AD.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Curcumina/química , Corantes Fluorescentes/síntese química , Imagem Óptica/métodos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Animais , Sítios de Ligação , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Curcumina/metabolismo , Feminino , Corantes Fluorescentes/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Simulação de Acoplamento Molecular , Agregados Proteicos , Espectroscopia de Luz Próxima ao InfravermelhoRESUMO
Hepsin is a type II transmembrane serine protease (TTSP) associated with cell proliferation and overexpressed in several types of cancer including prostate cancer (PCa). Because of its significant role in cancer progression and metastasis, hepsin is an attractive protein as a potential therapeutic and diagnostic biomarker for PCa. Based on the reported Leu-Arg dipeptide-based hepsin inhibitors, we performed structural modification and determined in vitro hepsin- and matriptase-inhibitory activities. Comprehensive structure-activity relationship studies identified that the p-guanidinophenylalanine-based dipeptide analog 22a exhibited a strong hepsin-inhibitory activity (Ki = 50.5 nM) and 22-fold hepsin selectivity over matriptase. Compound 22a could be a prototype molecule for structural optimization of dipeptide-based hepsin inhibitors.
Assuntos
Dipeptídeos/química , Serina Endopeptidases/metabolismo , Inibidores de Serina Proteinase/química , Domínio Catalítico , Dipeptídeos/metabolismo , Desenho de Fármacos , Ensaios Enzimáticos , Humanos , Simulação de Acoplamento Molecular , Fenilalanina/análogos & derivados , Fenilalanina/química , Ligação Proteica , Serina Endopeptidases/química , Inibidores de Serina Proteinase/metabolismo , Relação Estrutura-AtividadeRESUMO
Ethyl acetate (EtOAc) fraction of the Inonotus obliquus (Hymenochaetaceae) significantly inhibited nitric oxide production in lipopolysaccharide (LPS)-induced murine BV2 microglial cells. A new triterpene, characterized as inonotusol H (1), was isolated from the EtOAc fraction using the bioactivity-guided fractionation together with four known triterpenes, inotodiol (2), trametenolic acid (3), inonotsutriols A (4), and inonotusol A (5). Among them, Compounds 2-4 significantly reduced LPS-induced nitric oxide production to 4.5 ± 0.8%, 47.4 ± 4.4%, and 2.8 ± 1.7%, respectively, at a concentration of 30 µM.
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Thymic stromal lymphopoietin (TSLP) plays an important role in the pathophysiology of various allergic diseases that are mediated by T helper cell type-2 (Th2) responses, including asthma and atopic dermatitis. The primary focus of this study was the identification of potent inhibitors of the TSLP signaling pathway for potential therapeutic use. The 80% methanol extract of Machilus thunbergii bark significantly inhibited the signal transducer and activator of transcription 5 (STAT5) phosphorylation in human mast cell (HMC)-1 cells. Through activity-guided isolation, three lignans (1-3) were obtained and identified as (+)-galbelgin (1), meso-dihydroguaiaretic acid (2), and machilin A (3). Among them, two lignans (1 and 2) significantly inhibited STAT5 phosphorylation and TSLP/TSLPR interaction, as determined by ELISA. Our results indicated that lignans isolated from M. thunbergii are a promising resource for the treatment of allergic diseases.
Assuntos
Citocinas/antagonistas & inibidores , Lauraceae/química , Lignanas/farmacologia , Linhagem Celular , Fosforilação/efeitos dos fármacos , Casca de Planta/química , Fator de Transcrição STAT5/metabolismo , Células Th2/efeitos dos fármacos , Linfopoietina do Estroma do TimoRESUMO
Combating influenza is one of the perennial global public health issues to be managed. Antiviral drugs are useful for the treatment of influenza in the absence of an appropriate vaccine. However, the appearance of resistant strains necessitates a constant search for new drugs. In this study, we investigated novel anti-influenza drug candidates using in vitro and in vivo assays. We identified anti-influenza hit compounds using a high-throughput screening method with a green fluorescent protein-tagged recombinant influenza virus. Through subsequent analyses of their cytotoxicity and pharmacokinetic properties, one candidate (IY7640) was selected for further evaluation. In a replication kinetics analysis, IY7640 showed greater inhibitory effects during the early phase of viral infection than the viral neuraminidase inhibitor oseltamivir. In addition, we observed that hemagglutinin (HA)-mediated membrane fusion was inhibited by IY7640 treatment, indicating that the HA stalk region, which is highly conserved across various (sub)types of influenza viruses, may be the molecular target of IY7640. In an escape mutant analysis in cells, amino acid mutations were identified at the HA stalk region of the 2009 pandemic H1N1 (pH1N1) virus. Even though the in vivo efficacy of IY7640 did not reach complete protection in a lethal challenge study in mice, these results suggest that IY7640 has potential to be developed as a new type of anti-influenza drug.IMPORTANCE Anti-influenza drugs with broad-spectrum efficacy against antigenically diverse influenza viruses can be highly useful when no vaccines are available. To develop new anti-influenza drugs, we screened a number of small molecules and identified a strong candidate, IY7640. When added at the time of or after influenza virus infection, IY7640 was observed to successfully inhibit or reduce viral replication in cells. We subsequently discovered that IY7640 targets the stalk region of the influenza HA protein, which exhibits a relatively high degree of amino acid sequence conservation across various (sub)types of influenza viruses. Furthermore, IY7640 was observed to block HA-mediated membrane fusion of H1N1, H3N2, and influenza B viruses in cells. Although it appears less effective against strains other than H1N1 subtype viruses in a challenge study in mice, we suggest that the small molecule IY7640 has potential to be optimized as a new anti-influenza drug.
Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Vírus da Influenza A Subtipo H1N1/fisiologia , Vacinas contra Influenza/administração & dosagem , Infecções por Orthomyxoviridae/prevenção & controle , Bibliotecas de Moléculas Pequenas/administração & dosagem , Animais , Chlorocebus aethiops , Modelos Animais de Doenças , Cães , Feminino , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/genética , Vacinas contra Influenza/farmacologia , Células Madin Darby de Rim Canino , Fusão de Membrana/efeitos dos fármacos , Camundongos , Mutação , Infecções por Orthomyxoviridae/imunologia , Bibliotecas de Moléculas Pequenas/farmacologia , Células Vero , Replicação Viral/efeitos dos fármacosRESUMO
Prostate-specific membrane antigen (PSMA) is a zinc-bound metalloprotease which is highly expressed in metastatic prostate cancer. It has been considered an excellent target protein for prostate cancer imaging and targeted therapy because it is a membrane protein and its active site is located in the extracellular region. We successfully synthesized and evaluated a novel PSMA ligand conjugated with BODIPY650/665. Compound 1 showed strong PSMA-inhibitory activity and selective uptake into PSMA-expressing tumors. Compound 1 has the potential to be utilized as a near infrared (NIR) optical imaging probe targeting PSMA-expressing cancers.
Assuntos
Compostos de Boro/química , Desenho de Fármacos , Corantes Fluorescentes/síntese química , Glutamato Carboxipeptidase II/antagonistas & inibidores , Animais , Antígenos de Superfície/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Corantes Fluorescentes/química , Glutamato Carboxipeptidase II/metabolismo , Humanos , Ligantes , Masculino , Camundongos , Simulação de Dinâmica Molecular , Imagem Óptica , Polietilenoglicóis/química , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Transplante HeterólogoRESUMO
Prostate-specific membrane antigen (PSMA), a type II membrane glycoprotein, is considered an excellent target for the diagnosis or treatment of prostate cancer. We previously investigated the effect of ß- and γ-amino acids with (S)- or (R)-configuration in the S1 pocket on the binding affinity for PSMA. However, comprehensive studies on the effect of α-amino acid with (R)-configuration in the S1' pocket has not been reported yet. We selected ZJ-43 (1) and DCIBzL (5) as templates and synthesized their analogues with (S)- or (R)-configuration in the P1 and P1' regions. The PSMA-inhibitory activities of compounds with altered chirality in the P1' region were dropped dramatically, with their IC50 values changing from nM to µM ranges. The compounds with (S)-configuration at both P1 and P1' regions were more potent than the others. The findings of this study may provide insights regarding the structural modification of PSMA inhibitor in the S1' binding pocket.
Assuntos
Aminoácidos/farmacologia , Glutamato Carboxipeptidase II/antagonistas & inibidores , Peptídeos/farmacologia , Aminoácidos/síntese química , Aminoácidos/química , Antígenos de Superfície/metabolismo , Relação Dose-Resposta a Droga , Glutamato Carboxipeptidase II/metabolismo , Humanos , Ligantes , Estrutura Molecular , Peptídeos/síntese química , Peptídeos/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Hepsin is a type II serine protease that is highly expressed in neoplastic prostate. It is an attractive biomarker for imaging metastatic prostate cancer because of its overexpression in advanced prostate cancer and the location of its active site on the cell surface. We designed and synthesized novel hepsin-targeted imaging probes by conjugating the hepsin-binding ligand with near-infrared (NIR) optical dyes. The Leu-Arg dipeptides, attached to BODIPY or SulfoCy7, exhibited strong hepsin-inhibitory activities with Ki values of 21 and 22â¯nM, respectively. Compound 2 showed selective uptake and retention in hepsin-overexpressing cells. This is the first report of hepsin-targeted optical probes with strong binding affinities and high selectivity over matriptase. Compound 2 has the potential to be used for developing hepsin-based imaging probes and be as a prototype molecule in the design of new hepsin inhibitors.
Assuntos
Desenho de Fármacos , Corantes Fluorescentes/química , Serina Endopeptidases/química , Inibidores de Serina Proteinase/química , Sítios de Ligação , Compostos de Boro/química , Domínio Catalítico , Linhagem Celular Tumoral , Humanos , Concentração Inibidora 50 , Ligantes , Simulação de Acoplamento Molecular , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Inibidores de Serina Proteinase/metabolismoRESUMO
MeCP2 is a chromatin associated protein which is highly expressed in brain and relevant with Rett syndrome (RTT). There are AT-hook motifs in MeCP2 which can bind with AT-rich DNA, suggesting a role in chromatin binding. Here, we report the identification and characterization of another AT-rich DNA binding motif (residues 295 to 313) from the C-terminal transcription repression domain of MeCP2 by nuclear magnetic resonance (NMR) and isothermal calorimetry (ITC). This motif shows a micromolar affinity to AT-rich DNA, and it binds to the minor groove of DNA like AT-hook motifs. Together with the previous studies, our results provide an insight into a critical role of this motif in chromatin structure and function.
Assuntos
DNA/metabolismo , Proteína 2 de Ligação a Metil-CpG/química , Proteína 2 de Ligação a Metil-CpG/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Sítios de Ligação , DNA/química , Humanos , Conformação de Ácido Nucleico , Ligação Proteica , Domínios Proteicos , Síndrome de Rett/metabolismoRESUMO
Thymic stromal lymphopoietin (TSLP) is a type II cytokine which is associated with most inflammatory allergic disorders in humans. It is produced mainly by epithelial cells with important role in the development of chronic inflammatory diseases by activating T-helper cell type-2 (TH2) pathways. In this study, a total of 16 peptides were prepared by solid phase peptide synthesis based on amino acid sequences of the interface between TSLP and TSLP receptor. Their TSLP inhibition activities were determined by ELISA assay. Among them, three peptides (6-8) exhibited >50% inhibition at concentration of 0.3mM. They can be used as hit compounds for developing peptide-based TSLP inhibitors.
Assuntos
Citocinas/antagonistas & inibidores , Peptídeos/metabolismo , Sequência de Aminoácidos , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Humanos , Ligantes , Peptídeos/química , Ligação Proteica , Receptores de Citocinas/química , Receptores de Citocinas/metabolismo , Células Th2/citologia , Células Th2/metabolismo , Linfopoietina do Estroma do TimoRESUMO
Hepsin, a type II transmembrane serine protease, is an attractive protein as a potential therapeutic and diagnostic biomarker for prostate cancer because it is highly up-regulated in prostate cancer and promotes both progression and metastasis. Starting from the reported tetrapeptide hepsin inhibitor Ac-KQLR-ketothiazole (kt) (1), we investigated the minimal structural requirements for hepsin inhibitory activity by truncating amino acids at the N-terminus. The kt and ketobenzothiazole (kbt) dipeptide analogs Ac-LR-kt (3) and Ac-LR-kbt (15) were found to be potent hepsin inhibitors, exhibiting Ki values of 22nM and 3nM, respectively. The present work suggests that LR-containing dipeptide molecules could be useful as lead compounds for the development of novel hepsin inhibitors.
Assuntos
Benzotiazóis/farmacologia , Dipeptídeos/farmacologia , Serina Endopeptidases/metabolismo , Inibidores de Serina Proteinase/farmacologia , Tiazóis/farmacologia , Benzotiazóis/síntese química , Dipeptídeos/síntese química , Humanos , Simulação de Acoplamento Molecular , Proteínas Recombinantes/metabolismo , Inibidores de Serina Proteinase/síntese química , Tiazóis/síntese químicaRESUMO
Olfactory receptors (ORs) are extensively expressed in olfactory as well as non-olfactory tissues. Although many OR transcripts are expressed in non-olfactory tissues, only a few studies demonstrate the functional role of ORs. Here, we verified that mouse pancreatic α-cells express potential OR-mediated downstream effectors. Moreover, high levels of mRNA for the olfactory receptors Olfr543, Olfr544, Olfr545, and Olfr1349 were expressed in α-cells as assessed using RNA-sequencing, microarray, and quantitative real-time RT-PCR analyses. Treatment with dicarboxylic acids (azelaic acid and sebacic acid) increased intracellular Ca(2+) mobilization in pancreatic α-cells. The azelaic acid-induced Ca(2+) response as well as glucagon secretion was concentration- and time-dependent manner. Olfr544 was expressed in α-cells, and the EC50 value of azelaic acid to Olfr544 was 19.97 µM, whereas Olfr545 did not respond to azelaic acid. Our findings demonstrate that Olfr544 responds to azelaic acid to regulate glucagon secretion through Ca(2+) mobilization in α-cells of the mouse pancreatic islets, suggesting that Olfr544 may be an important therapeutic target for metabolic diseases.
Assuntos
Ácidos Dicarboxílicos/farmacologia , Glucagon/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Animais , Linhagem Celular , Ilhotas Pancreáticas/metabolismo , CamundongosRESUMO
Novel pyrone-derived quorum sensing (QS) ligands to inhibit the binding of OdDHL to the LasR of Pseudomonas aeruginosa were designed, synthesized and evaluated. Among the analogs, the most potent compound 8 exhibited strong in vitro inhibitory activities against biofilm formation and down-regulated OdDHL/LasR-associated genes by 35-67%. The binding mode of 8 in silico was highly similar to that of the crystal ligand OdDHL in the active site of LasR.
Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Biofilmes/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Pironas/farmacologia , Percepção de Quorum/efeitos dos fármacos , Transativadores/metabolismo , 4-Butirolactona/análogos & derivados , 4-Butirolactona/metabolismo , Antibacterianos/química , Homosserina/análogos & derivados , Homosserina/metabolismo , Humanos , Simulação de Acoplamento Molecular , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/prevenção & controle , Pseudomonas aeruginosa/fisiologia , Pironas/química , Relação Estrutura-AtividadeRESUMO
Glutamate carboxypeptidase II (GCPII) is a zinc metalloprotease on the surface of astrocytes which cleaves N-acetylaspartylglutamate to release N-acetylaspartate and glutamate. GCPII inhibitors can decrease glutamate concentration and play a protective role against apoptosis or degradation of brain neurons. Herein, we report the synthesis and structural analysis of novel carborane-based GCPII inhibitors. We determined the X-ray crystal structure of GCPII in complex with a carborane-containing inhibitor at 1.79Å resolution. The X-ray analysis revealed that the bulky closo-carborane cluster is located in the spacious entrance funnel region of GCPII, indicating that the carborane cluster can be further structurally modified to identify promising lead structures of novel GCPII inhibitors.