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1.
Pharm Res ; 40(6): 1553-1568, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37173537

RESUMO

BACKGROUND: Chronic Obstructive Pulmonary Disease is characterised by declining lung function and a greater oxidative stress burden due to reduced activity of antioxidant enzymes such as Glutathione Peroxidase 1. OBJECTIVES: The extent to which drugs may contribute to this compromised activity is largely unknown. An integrative drug safety model explores inhibition of Glutathione Peroxidase 1 by drugs and their association with chronic obstructive pulmonary disease adverse drug events. METHODS: In silico molecular modelling approaches were utilised to predict the interactions that drugs have within the active site of Glutathione Peroxidase 1 in both human and bovine models. Similarities of chemical features between approved drugs and the known inhibitor tiopronin were also investigated. Subsequently the Food and Drug Administration Adverse Event System was searched to uncover adverse drug event signals associated with chronic obstructive pulmonary disease. RESULTS: Statistical and molecular modelling analyses confirmed that the use of several registered drugs, including acetylsalicylic acid and atenolol may be associated with inhibition of Glutathione Peroxidase 1 and chronic obstructive pulmonary disease. CONCLUSION: The integration of molecular modelling and pharmacoepidemological data has the potential to advance drug safety science. Ongoing review of medication use and further pharmacoepidemiological and biological analyses are warranted to ensure appropriate use is recommended.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Doença Pulmonar Obstrutiva Crônica , Animais , Bovinos , Humanos , Glutationa Peroxidase GPX1 , Glutationa , Glutationa Peroxidase/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico
2.
Bioorg Med Chem ; 80: 117158, 2023 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-36706608

RESUMO

Deregulation of cyclin-dependent kinase 2 (CDK2) and its activating partners, cyclins A and E, is associated with the pathogenesis of a myriad of human cancers and with resistance to anticancer drugs including CDK4/6 inhibitors. Thus, CDK2 has become an attractive target for the development of new anticancer therapies and for the amelioration of the resistance to CDK4/6 inhibitors. Bioisosteric replacement of the thiazole moiety of CDKI-73, a clinically trialled CDK inhibitor, by a pyrazole group afforded 9 and 19 that displayed potent CDK2-cyclin E inhibition (Ki = 0.023 and 0.001 µM, respectively) with submicromolar antiproliferative activity against a panel of cancer cell lines (GI50 = 0.025-0.780 µM). Mechanistic studies on 19 with HCT-116 colorectal cancer cells revealed that the compound reduced the phosphorylation of retinoblastoma at Ser807/811, arrested the cells at the G2/M phase, and induced apoptosis. These results highlight the potential of the 2-anilino-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine series in developing potent and selective CDK2 inhibitors to combat cancer.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Quinase 2 Dependente de Ciclina , Quinases Ciclina-Dependentes/metabolismo , Antineoplásicos/farmacologia , Pirimidinas/farmacologia , Pirazóis/farmacologia
3.
Molecules ; 28(7)2023 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-37049714

RESUMO

Cyclin-dependent kinase 2 (CDK2) has been garnering considerable interest as a target to develop new cancer treatments and to ameliorate resistance to CDK4/6 inhibitors. However, a selective CDK2 inhibitor has yet to be clinically approved. With the desire to discover novel, potent, and selective CDK2 inhibitors, the phenylsulfonamide moiety of our previous lead compound 1 was bioisosterically replaced with pyrazole derivatives, affording a novel series of N,4-di(1H-pyrazol-4-yl)pyrimidin-2-amines that exhibited potent CDK2 inhibitory activity. Among them, 15 was the most potent CDK2 inhibitor (Ki = 0.005 µM) with a degree of selectivity over other CDKs tested. Meanwhile, this compound displayed sub-micromolar antiproliferative activity against a panel of 13 cancer cell lines (GI50 = 0.127-0.560 µM). Mechanistic studies in ovarian cancer cells revealed that 15 reduced the phosphorylation of retinoblastoma at Thr821, arrested cells at the S and G2/M phases, and induced apoptosis. These results accentuate the potential of the N,4-di(1H-pyrazol-4-yl)pyrimidin-2-amine scaffold to be developed into potent and selective CDK2 inhibitors for the treatment of cancer.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Quinase 2 Dependente de Ciclina , Relação Estrutura-Atividade , Aminas/farmacologia , Antineoplásicos/farmacologia , Pirazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Estrutura Molecular
4.
Pharmacol Res ; 180: 106249, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35533805

RESUMO

Cyclin-dependent kinase 3 (CDK3) is a major player driving retinoblastoma (Rb) phosphorylation during the G0/G1 transition and in the early G1 phase of the cell cycle, preceding the effects of CDK4/cyclin D, CDK6/cyclin D, and CDK2/cyclin E. CDK3 can also directly regulate the activity of E2 factor (E2F) by skipping the role of Rb in late G1, potentially via the phosphorylation of the E2F1 partner DP1. Beyond the cell cycle, CDK3 interacts with various transcription factors involved in cell proliferation, differentiation, and transformation driven by the epidermal growth factor receptor (EGFR)/rat sarcoma virus (Ras) signaling pathway. The expression of CDK3 is extremely low in normal human tissue but upregulated in many cancers, implying a profound role in oncogenesis. Further evaluation of this role has been hampered by the lack of selective pharmacological inhibitors. Herein, we provide a comprehensive overview about the therapeutic potential of targeting CDK3 in cancer.


Assuntos
Neoplasias , Animais , Ciclo Celular , Ciclina D/metabolismo , Quinase 3 Dependente de Ciclina/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Fosforilação
5.
J Clin Pharm Ther ; 46(6): 1687-1694, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34431531

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Proton pump inhibitors (PPIs), used to treat and prevent gastro-oesophageal conditions, are well-tolerated but have been associated with risk including pneumonia. The extent to which initiation of PPIs can contribute to other respiratory conditions such as chronic obstructive pulmonary disease (COPD) is largely unknown. METHODS: A sequence symmetry analysis (SSA) approach was applied to the Australian Department of Human Services, Pharmaceutical Benefits Scheme 10% extract. Participants were aged 45 years and older and were dispensed PPIs (ATC Codes A02BC01, A02BC02, A02BC03, A02BC04 and A02BC05) and long-acting bronchodilators (LABDs) for COPD (ATC Codes R03BB04 (PBS Item Code 10509D and 08626B), R03BB05, R03BB06, R03BB07 and R03AC18 (PBS Item Code 05137J and 05134F)) between 2013 and 2019. The analysis included patients initiated on an LABD within 12 months before or after their first prescription of a PPI. The crude sequence ratio (cSR) was calculated as the number of patients prescribed their first LABD after starting a PPI divided by the number of patients prescribed their first LABD before starting a PPI. Calculation of the adjusted sequence ratio (aSR) accounted for prescribing trends over time in initiation of each of the medicines. A signal was identified where the aSR lower 95% confidence interval (CI) was greater than one. RESULTS AND DISCUSSION: Initiation of omeprazole was associated with a 29% increased risk of initiating a LABD (ASR = 1.29 95% CI 1.22-1.36). Initiation of esomeprazole, rabeprazole, pantoprazole or lansoprazole was associated with 25%, 15%, 8% and 8% increased risk, respectively. WHAT IS NEW AND CONCLUSION: There is an established association between gastro-oesophageal reflux disease and COPD which has been confirmed by implementation of a sequence symmetry-based approach which demonstrated that PPI initiation is potentially associated with progression or exacerbation of COPD. The impact PPI use has directly on this association requires further investigation.


Assuntos
Broncodilatadores/administração & dosagem , Inibidores da Bomba de Prótons/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/etiologia , Idoso , Broncodilatadores/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Bomba de Prótons/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/epidemiologia
6.
Bioorg Chem ; 105: 104394, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33120321

RESUMO

Novel 4-substituted quinazoline-2-carboxamide derivatives targeting AcrB were designed, synthesized and evaluated for their biological activity as AcrB inhibitors. In particular, the ability of the compounds to potentiate the activity of antibiotics, to inhibit Nile Red efflux and to target AcrB was investigated. In this study, 19 compounds were identified to reduce the MIC values of at least one tested antibacterial by 2- to 16-fold at a lower concentration. Identified modulating compounds also possessed considerable inhibition on Nile red efflux at concentrations as low as 50 µM and did not display off-target effects on the outer membrane. Among the above compounds with characteristics of ideal AcrB inhibitors, the most outstanding ones are A15 and B5-B7. In particular, A15 and B7 exhibited not only the most prominent performance in the synergistic effect, but also completely abolished Nile Red efflux at concentrations of 50 and 100 µM, respectively. In docking simulations, A15 was observed to have the most favorable docking score and was predicted to bind in the hydrophobic trap as has been noted with other inhibitors such as MBX2319. It is worth noting that the 4-morpholinoquinazoline-2-carboxamide core appears to be a promising chemical skeleton to be further optimized for the discovery of more potent AcrB inhibitors.


Assuntos
Antibacterianos/farmacologia , Desenho de Fármacos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Proteínas de Escherichia coli/antagonistas & inibidores , Escherichia coli/efeitos dos fármacos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Quinazolinas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Células HeLa , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade
7.
Bioorg Med Chem ; 27(2): 436-441, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30581047

RESUMO

The 26S proteasome and calpain are linked to a number of important human diseases. Here, we report a series of analogues of the prototypical tripeptide aldehyde inhibitor MG132 that show a unique combination of high activity and selectivity for calpains over proteasome. Tripeptide aldehydes (1-3) with an aromatic P3 substituent show enhanced activity and selectivity against ovine calpain 2 relative to chymotrypsin-like activity of proteasome. Docking studies reveal the key contacts between inhibitors and calpain to confirm the importance of the S3 pocket with respect to selectivity between calpains 1 and 2 and the proteasome.


Assuntos
Inibidores de Cisteína Proteinase/farmacologia , Leupeptinas/farmacologia , Inibidores de Proteassoma/farmacologia , Animais , Antimaláricos/síntese química , Antimaláricos/química , Antimaláricos/farmacologia , Calpaína/química , Domínio Catalítico , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/química , Leupeptinas/síntese química , Leupeptinas/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Plasmodium falciparum/enzimologia , Complexo de Endopeptidases do Proteassoma/química , Inibidores de Proteassoma/síntese química , Inibidores de Proteassoma/química , Conformação Proteica , Ratos , Ovinos , Suínos
8.
J Chem Inf Model ; 57(3): 413-416, 2017 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-28191946

RESUMO

Aberrant activity of cyclin-dependent kinase (CDK) 8 is implicated in various cancers. While CDK8-targeting anticancer drugs are highly sought-after, no CDK8 inhibitor has yet reached clinical trials. Herein a large library of drug-like molecules was computationally screened using two complementary cascades to identify potential CDK8 inhibitors. Thirty-three hits were identified to inhibit CDK8 and seven of them were active against colorectal cancer cell lines. Finally, the primary target was confirmed using three promising hits.


Assuntos
Quinase 8 Dependente de Ciclina/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores de Proteínas Quinases/farmacologia , Linhagem Celular Tumoral , Quinase 8 Dependente de Ciclina/química , Quinase 8 Dependente de Ciclina/metabolismo , Humanos , Inibidores de Proteínas Quinases/metabolismo , Interface Usuário-Computador
9.
Xenobiotica ; 47(6): 461-469, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27412850

RESUMO

1. The metabolism of the anti-inflammatory diterpenoid polyandric acid A (PAA), a constituent of the Australian Aboriginal medicinal plant Dodonaea polyandra, and its de-esterified alcohol metabolite, hydrolysed polyandric acid A (PAAH) was studied in vitro using human liver microsomes (HLM) and recombinant UDP-glucuronosyltransferase (UGT) and cytochrome P450 (CYP) enzymes. 2. Hydrolysis of PAA to yield PAAH occurred upon incubation with HLM. Further incubations of PAAH with HLM in the presence of UGT and CYP cofactors resulted in significant depletion, with UGT-mediated depletion as the major pathway. 3. Reaction phenotyping utilising selective enzyme inhibitors and recombinant human UGT and CYP enzymes revealed UGT2B7 and UGT1A1, and CYP2C9 and CYP3A4 as the major enzymes involved in the metabolism of PAAH. 4. Analysis of incubations of PAAH with UDP-glucuronic acid-supplemented HLM and recombinant enzymes by UPLC/MS/MS identified three glucuronide metabolites. The metabolites were further characterised by ß-glucuronidase and mild alkaline hydrolysis. The acyl glucuronide of PAAH was shown to be the major metabolite. 5. This study demonstrates the in vitro metabolism of PAA and PAAH and represents the first systematic study of the metabolism of an active constituent of an Australian Aboriginal medicinal plant.


Assuntos
Anti-Inflamatórios/metabolismo , Diterpenos Clerodânicos/metabolismo , Microssomos Hepáticos/metabolismo , Austrália , Sistema Enzimático do Citocromo P-450/metabolismo , Glucuronídeos/metabolismo , Glucuronosiltransferase/metabolismo , Humanos , Oxirredução
10.
Exp Eye Res ; 146: 212-223, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26997634

RESUMO

Pseudoexfoliation (PEX) syndrome is a systemic disease involving the extracellular matrix. It increases the risk of glaucoma, an irreversible cause of blindness, and susceptibility to heart disease, stroke and hearing loss. Single nucleotide polymorphisms (SNPs) in the LOXL1 (Lysyl oxidase-like 1) gene are the major known genetic risk factor for PEX syndrome. Two coding SNPs, rs1048861 (G > T; Arg141Leu) and rs3825942 (G > A; Gly153Asp), in the LOXL1 gene are strongly associated with the disease risk in multiple populations worldwide. In the present study, we investigated functional effects of these SNPs on the LOXL1 protein. We show through molecular modelling that positions 141 and 153 are likely surface residues and hence possible recognition sites for protein-protein interactions; the Arg141Leu and Gly153Asp substitutions cause charge changes that would lead to local differences in protein electrostatic potential and in turn the potential to modify protein-protein interactions. In RFL-6 rat fetal lung fibroblast cells ectopically expressing the LOXL1 protein variants related to PEX (Arg141_Gly153, Arg141_Asp153 or Leu141_Gly153), immunoprecipitation of the secreted variants showed differences in their processing by endogenous proteins, possibly Bone morphogenetic protein-1 (BMP-1) that cleaves and leads to enzymatic activation of LOXL1. Immunofluorescence labelling of the ectopically expressed protein variants in RFL-6 cells showed no significant difference in their extracellular accumulation tendency. In conclusion, this is the first report of a biological effect of the coding SNPs in the LOXL1 gene associated with PEX syndrome, on the LOXL1 protein. The findings indicate that the disease associated coding variants themselves may be involved in the manifestation of PEX syndrome.


Assuntos
Aminoácido Oxirredutases/genética , Síndrome de Exfoliação/genética , Aminoácido Oxirredutases/química , Aminoácido Oxirredutases/metabolismo , Animais , Proteína Morfogenética Óssea 1/metabolismo , Linhagem Celular , Síndrome de Exfoliação/metabolismo , Predisposição Genética para Doença , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Ratos , Fatores de Risco
11.
Mol Pharmacol ; 88(2): 380-9, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26044548

RESUMO

The Ras/Raf/MAPK and PI3K/Akt/mTOR pathways are key signaling cascades involved in the regulation of cell proliferation and survival, and have been implicated in the pathogenesis of several types of cancers, including acute myeloid leukemia (AML). The oncogenic activity of eIF4E driven by the Mnk kinases is a convergent determinant of the two cascades, suggesting that targeting the Mnk/eIF4E axis may provide therapeutic opportunity for the treatment of cancer. Herein, a potent and selective Mnk2 inhibitor (MNKI-85) and a dual-specific Mnk1 and Mnk2 inhibitor (MNKI-19), both derived from a thienopyrimidinyl chemotype, were selected to explore their antileukemic properties. MNKI-19 and MNKI-85 are effective in inhibiting the growth of AML cells that possess an M5 subtype with FLT3-internal tandem duplication mutation. Further mechanistic studies show that the downstream effects with respect to the selective Mnk1/2 kinase inhibition in AML cells causes G1 cell cycle arrest followed by induction of apoptosis. MNKI-19 and MNKI-85 demonstrate similar Mnk2 kinase activity and cellular antiproliferative activity but exhibit different time-dependent effects on cell cycle progression and apoptosis. Collectively, this study shows that pharmacologic inhibition of both Mnk1 and Mnk2 can result in a more pronounced cellular response than targeting Mnk2 alone. However, MNKI-85, a first-in-class inhibitor of Mnk2, can be used as a powerful pharmacologic tool in studying the Mnk2/eIF4E-mediated tumorigenic mechanism. In conclusion, this study provides a better understanding of the mechanism underlying the inhibition of AML cell growth by Mnk inhibitors and suggests their potential utility as a therapeutic agent for AML.


Assuntos
Antineoplásicos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Leucemia Mieloide Aguda/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Tiofenos/farmacologia , Antineoplásicos/síntese química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Células HL-60 , Humanos , Mutação , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/síntese química , Tiofenos/síntese química , Tirosina Quinase 3 Semelhante a fms/genética
12.
PLoS Genet ; 8(6): e1002755, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22719265

RESUMO

Mitochondrial translation, essential for synthesis of the electron transport chain complexes in the mitochondria, is governed by nuclear encoded genes. Polymorphisms within these genes are increasingly being implicated in disease and may also trigger adverse drug reactions. Statins, a class of HMG-CoA reductase inhibitors used to treat hypercholesterolemia, are among the most widely prescribed drugs in the world. However, a significant proportion of users suffer side effects of varying severity that commonly affect skeletal muscle. The mitochondria are one of the molecular targets of statins, and these drugs have been known to uncover otherwise silent mitochondrial mutations. Based on yeast genetic studies, we identify the mitochondrial translation factor MEF2 as a mediator of atorvastatin toxicity. The human ortholog of MEF2 is the Elongation Factor Gene (EF-G) 2, which has previously been shown to play a specific role in mitochondrial ribosome recycling. Using small interfering RNA (siRNA) silencing of expression in human cell lines, we demonstrate that the EF-G2mt gene is required for cell growth on galactose medium, signifying an essential role for this gene in aerobic respiration. Furthermore, EF-G2mt silenced cell lines have increased susceptibility to cell death in the presence of atorvastatin. Using yeast as a model, conserved amino acid variants, which arise from non-synonymous single nucleotide polymorphisms (SNPs) in the EF-G2mt gene, were generated in the yeast MEF2 gene. Although these mutations do not produce an obvious growth phenotype, three mutations reveal an atorvastatin-sensitive phenotype and further analysis uncovers a decreased respiratory capacity. These findings constitute the first reported phenotype associated with SNPs in the EF-G2mt gene and implicate the human EF-G2mt gene as a pharmacogenetic candidate gene for statin toxicity in humans.


Assuntos
Respiração Celular/genética , Ácidos Heptanoicos/farmacologia , Mitocôndrias/metabolismo , Fator G para Elongação de Peptídeos , Fatores de Alongamento de Peptídeos/genética , Pirróis/farmacologia , Proteínas de Saccharomyces cerevisiae/genética , Atorvastatina , Morte Celular/genética , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Mitocôndrias/genética , Fator G para Elongação de Peptídeos/genética , Fator G para Elongação de Peptídeos/metabolismo , Fator G para Elongação de Peptídeos/fisiologia , Fatores de Alongamento de Peptídeos/metabolismo , Polimorfismo de Nucleotídeo Único , RNA Interferente Pequeno , Ribossomos/genética , Ribossomos/metabolismo , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo
13.
Drug Saf ; 47(1): 59-70, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37995048

RESUMO

BACKGROUND AND OBJECTIVE: Prior molecular modelling analysis identified several medicines as potential inhibitors of glutathione peroxidase 1 (GPx1) which may contribute to development or progression of chronic obstructive pulmonary disease (COPD). This study investigates 40 medicines (index medicines) for signals of COPD development or progression in a real-world dataset. METHODS: Sequence symmetry analysis (SSA) was conducted using a 10% extract of Australian Pharmaceutical Benefits Scheme (PBS) claims data between January 2013 and September 2019. Patients must have been initiated on an index medicine and a medicine for COPD development or progression within 12 months of each other. Sequence ratios were calculated as the number of patients who initiated an index medicine followed by a medicine for COPD development or progression divided by the number who initiated the index medicine second. An adjusted sequence ratio (aSR) was calculated which accounted for changes in prescribing trends. Adverse drug event signals (ADEs) were identified where the aSR lower 95% confidence interval (CI) was greater than 1. RESULTS: Twenty-one of 40 (53%) index medicines had at least one ADE signal of COPD development or progression. Signals of COPD development, as identified using initiation of tiotropium, were observed for atenolol (aSR 1.32, 95% CI 1.23-1.42) and naproxen (aSR 1.14, 95% CI 1.06-1.23). Several signals of COPD progression were observed, including initiation of fluticasone propionate/salmeterol following initiation of atenolol (aSR 1.44, 95% CI 1.30-1.60) and initiation of aclidinium/formoterol following initiation of naproxen (aSR 2.21, 95% CI 1.34-3.65). CONCLUSION: ADE signals were generated for several potential GPx1 inhibitors; however, further validation of signals is required in large well-controlled observational studies.


Assuntos
Prescrições de Medicamentos , Inibidores Enzimáticos , Glutationa Peroxidase GPX1 , Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Glutationa Peroxidase GPX1/antagonistas & inibidores , Revisão da Utilização de Seguros/estatística & dados numéricos , Austrália , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/uso terapêutico , Prescrições de Medicamentos/estatística & dados numéricos , Progressão da Doença
14.
Hum Mutat ; 34(3): 435-8, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23255486

RESUMO

Congenital cataract is a heterogeneous disorder causing severe visual impairment in affected children. We screened four South Australian families with autosomal dominant congenital cataract for mutations in 10 crystallin genes known to cause congenital cataract. We identified a novel segregating heterozygous mutation, c.62G>A (p.R21Q), in the CRYΑA gene in one family. Western blotting of proteins freshly extracted from cataractous lens material of the proband demonstrated a marked reduction in the amount of the high-molecular-weight oligomers seen in the lens material of an unaffected individual. We conclude that the p.R21Q mutation, which is located in the highly conserved and structurally significant N-terminal region of the protein, is responsible for the cataract phenotype observed in the family as this mutation likely reduces the formation of the functional oligomeric alpha-crystallin.


Assuntos
Catarata/congênito , Catarata/genética , Cristalinas/genética , Mutação de Sentido Incorreto , alfa-Cristalinas/genética , Western Blotting , Genes Dominantes , Heterozigoto , Humanos , Havaiano Nativo ou Outro Ilhéu do Pacífico/genética , Linhagem , Fenótipo , Austrália do Sul
15.
Chemistry ; 19(24): 7975-81, 2013 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-23606616

RESUMO

Peptide-derived protease inhibitors are an important class of compounds with the potential to treat a wide range of diseases. Herein, we describe the synthesis of a series of triazole-containing macrocyclic protease inhibitors pre-organized into a ß-strand conformation and an evaluation of their activity against a panel of proteases. Acyclic azido-alkyne-based aldehydes are also evaluated for comparison. The macrocyclic peptidomimetics showed considerable activity towards calpain II, cathepsin L and S, and the 20S proteasome chymotrypsin-like activity. Some of the first examples of highly potent macrocyclic inhibitors of cathepsin S were identified. These adopt a well-defined ß-strand geometry as shown by NMR spectroscopy, X-ray analysis, and molecular docking studies.


Assuntos
Compostos Macrocíclicos/síntese química , Peptídeos/química , Inibidores de Proteases/síntese química , Triazóis/síntese química , Calpaína/antagonistas & inibidores , Catepsina L/antagonistas & inibidores , Química Click , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Conformação Molecular , Ressonância Magnética Nuclear Biomolecular , Peptidomiméticos , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Triazóis/química , Triazóis/farmacologia
16.
ACS Infect Dis ; 9(12): 2504-2522, 2023 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-37888944

RESUMO

The inhibition of efflux pumps is a promising approach to combating multidrug-resistant bacteria. We have developed a combined structure- and ligand-based model, using OpenEye software, for the identification of inhibitors of AcrB, the inner membrane protein component of the AcrAB-TolC efflux pump in Escherichia coli. From a database of 1391 FDA-approved drugs, 23 compounds were selected to test for efflux inhibition in E. coli. Seven compounds, including ivacaftor (25), butenafine (19), naftifine (27), pimozide (30), thioridazine (35), trifluoperazine (37), and meloxicam (26), enhanced the activity of at least one antimicrobial substrate and inhibited the efflux pump-mediated removal of the substrate Nile Red from cells. Ivacaftor (25) inhibited efflux dose dependently, had no effect on an E. coli strain with genomic deletion of the gene encoding AcrB, and did not damage the bacterial outer membrane. In the presence of a sub-minimum inhibitory concentration (MIC) of the outer membrane permeabilizer colistin, ivacaftor at 1 µg/mL reduced the MICs of erythromycin and minocycline by 4- to 8-fold. The identification of seven potential AcrB inhibitors shows the merits of a combined structure- and ligand-based approach to virtual screening.


Assuntos
Proteínas de Escherichia coli , Escherichia coli , Proteínas de Escherichia coli/metabolismo , Ligantes , Proteínas de Membrana Transportadoras/metabolismo , Proteínas da Membrana Bacteriana Externa/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Antibacterianos/química , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo
17.
Front Microbiol ; 13: 967949, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36106080

RESUMO

Acinetobacter baumannii is a pathogen with high intrinsic antimicrobial resistance while multidrug resistant (MDR) and extensively drug resistant (XDR) strains of this pathogen are emerging. Treatment options for infections by these strains are very limited, hence new therapies are urgently needed. The bacterial cell division protein, FtsZ, is a promising drug target for the development of novel antimicrobial agents. We have previously reported limited activity of cinnamaldehyde analogs against Escherichia coli. In this study, we have determined the antimicrobial activity of six cinnamaldehyde analogs for antimicrobial activity against A. baumannii. Microscopic analysis was performed to determine if the compounds inhibit cell division. The on-target effect of the compounds was assessed by analyzing their effect on polymerization and on the GTPase activity of purified FtsZ from A. baumannii. In silico docking was used to assess the binding of cinnamaldehyde analogs. Finally, in vivo and in vitro safety assays were performed. All six compounds displayed antibacterial activity against the critical priority pathogen A. baumannii, with 4-bromophenyl-substituted 4 displaying the most potent antimicrobial activity (MIC 32 µg/mL). Bioactivity was significantly increased in the presence of an efflux pump inhibitor for A. baumannii ATCC 19606 (up to 32-fold) and significantly, for extensively drug resistant UW 5075 (greater than 4-fold), suggesting that efflux contributes to the intrinsic resistance of A. baumannii against these agents. The compounds inhibited cell division in A. baumannii as observed by the elongated phenotype and targeted the FtsZ protein as seen from the inhibition of polymerization and GTPase activity. In silico docking predicted that the compounds bind in the interdomain cleft adjacent to the H7 core helix. Di-chlorinated 6 was devoid of hemolytic activity and cytotoxicity against mammalian cells in vitro, as well as adverse activity in a Caenorhabditis elegans nematode model in vivo. Together, these findings present halogenated analogs 4 and 6 as promising candidates for further development as antimicrobial agents aimed at combating A. baumannii. This is also the first report of FtsZ-targeting compounds with activity against an XDR A. baumannii strain.

18.
Biomolecules ; 12(7)2022 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-35883516

RESUMO

The regulation of vitamin D3 actions in humans occurs mainly through the Cytochrome P450 24-hydroxylase (CYP24A1) enzyme activity. CYP24A1 hydroxylates both 25-hydroxycholecalciferol (25(OH)D3) and 1,25-dihydroxycholecalciferol (1,25(OH)2D3), which is the first step of vitamin D catabolism. An abnormal status of the upregulation of CYP24A1 occurs in many diseases, including chronic kidney disease (CKD). CYP24A1 upregulation in CKD and diminished activation of vitamin D3 contribute to secondary hyperparathyroidism (SHPT), progressive bone deterioration, and soft tissue and cardiovascular calcification. Previous studies have indicated that CYP24A1 inhibition may be an effective strategy to increase endogenous vitamin D activity and decrease SHPT. This study has designed and synthesized a novel C-24 O-methyloxime analogue of vitamin D3 (VD1-6) to have specific CYP24A1 inhibitory properties. VD1-6 did not bind to the vitamin D receptor (VDR) in concentrations up to 10-7 M, assessed by a VDR binding assay. The absence of VDR binding by VD1-6 was confirmed in human embryonic kidney HEK293T cultures through the lack of CYP24A1 induction. However, in silico docking experiments demonstrated that VD1-6 was predicted to have superior binding to CYP24A1, when compared to that of 1,25(OH)2D3. The inhibition of CYP24A1 by VD1-6 was also evident by the synergistic potentiation of 1,25(OH)2D3-mediated transcription and reduced 1,25(OH)2D3 catabolism over 24 h. A further indication of CYP24A1 inhibition by VD1-6 was the reduced accumulation of the 24,25(OH)D3, the first metabolite of 25(OH)D catabolism by CYP24A1. Our findings suggest the potent CYP24A1 inhibitory properties of VD1-6 and its potential for testing as an alternative therapeutic candidate for treating SHPT.


Assuntos
Colecalciferol , Insuficiência Renal Crônica , Colecalciferol/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Células HEK293 , Humanos , Oximas , Receptores de Calcitriol/metabolismo , Vitamina D , Vitamina D3 24-Hidroxilase/metabolismo
19.
Drug Saf ; 44(3): 291-312, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33354752

RESUMO

INTRODUCTION: Antidepressant use during the first trimester is reported in 4-8% of pregnancies. The use of some selective serotonin reuptake inhibitors during the first trimester has been identified as increasing the odds for congenital heart defects; however, little is known about the safety of non-selective serotonin reuptake inhibitor antidepressants. OBJECTIVE: The objective of this study was to assess the odds of congenital heart defects associated with the use of antidepressants during the first trimester of pregnancy, and to update the literature as newer studies have been published since the latest systematic literature review and meta-analysis. METHODS: PubMed and Embase were searched till 3 June, 2020. Study quality was assessed, and study details were extracted. Meta-analyses were performed using RevMan 5.4, which assessed: (1) any antidepressant usage; (2) classes of antidepressants; and (3) individual antidepressants. RESULTS: Twenty studies were identified, encompassing 5,337,223 pregnancies. The odds ratio for maternal use of any antidepressant during the first trimester of pregnancy and the presence of congenital heart defects from the random effects meta-analysis was 1.28 (95% confidence interval [CI] 1.17-1.41). Significant odds ratios of 1.69 (95% CI 1.37-2.10) and 1.25 (95% CI 1.15-1.37) were reported for serotonin norepinephrine reuptake inhibitors and selective serotonin reuptake inhibitors, respectively. A non-statistically significant odds ratio of 1.02 (95% CI 0.82-1.25) was reported for the tricyclic antidepressants. Analyses of individual SSRIs produced significant odds ratios of 1.57 (95% CI 1.25-1.97), 1.36 (95% CI 1.08-1.72), and 1.29 (95% CI 1.14-1.45) for paroxetine, fluoxetine, and sertraline, respectively. The norepinephrine-dopamine-reuptake inhibitor bupropion also produced a significant odds ratio of 1.23 (95% CI 1.01-1.49). CONCLUSIONS: The selective serotonin reuptake inhibitor and serotonin norepinephrine reuptake inhibitor classes of antidepressants pose a greater risk for causing congenital heart defects than the tricyclic antidepressants. However, this risk for individual antidepressants within each class varies, and information regarding some antidepressants is still lacking.


Assuntos
Cardiopatias Congênitas , Inibidores Seletivos de Recaptação de Serotonina , Antidepressivos/efeitos adversos , Antidepressivos Tricíclicos , Feminino , Cardiopatias Congênitas/induzido quimicamente , Cardiopatias Congênitas/epidemiologia , Humanos , Norepinefrina , Gravidez , Serotonina , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos
20.
Neuropharmacology ; 198: 108755, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34416268

RESUMO

Excitatory and inhibitory neurotransmission within the spinal dorsal horn is tightly controlled to regulate transmission of nociceptive signals to the brain. One aspect of this control is modulation of neuronal activity through cholinergic signaling. Nociceptive neurons in the dorsal horn express both nicotinic and muscarinic cholinergic receptors and activation of these receptors reduces pain in humans, while inhibition leads to nociceptive hypersensitivity. At a cellular level, acetylcholine (ACh) has diverse effects on excitability which is dependent on the receptor and neuronal subtypes involved. In the present study we sought to characterize the electrophysiological responses of specific subsets of lamina II interneurons from rat and marmoset spinal cord. Neurons were grouped by morphology and by action potential firing properties. Whole-cell voltage-clamp recordings from lamina II dorsal horn neurons of adult rats showed that bath applied acetylcholine increased, decreased or had no effect on spontaneous synaptic current activity in a cell-type specific manner. ACh modulated inhibitory synaptic activity in 80% of neurons, whereas excitatory synaptic activity was affected in less than 50% of neurons. In whole-cell current clamp recordings, brief somatic application of ACh induced cell-type specific responses in 79% of rat lamina II neurons, which included: depolarization and action potential firing, subthreshold membrane depolarization, biphasic responses characterized by transient depolarization followed by hyperpolarization and membrane hyperpolarization alone. Similar responses were seen in marmoset lamina II neurons and the properties of each neuron group were consistent across species. ACh-induced hyperpolarization was blocked by the muscarinic antagonist atropine and all forms of acetylcholine-induced depolarization were blocked by the nicotinic antagonist mecamylamine. The cholinergic system plays an important role in regulating nociception and this study contributes to our understanding of how circuit activity is controlled by ACh at a cellular level in primate and rodent spinal cord.


Assuntos
Acetilcolina/farmacologia , Rede Nervosa/efeitos dos fármacos , Células do Corno Posterior/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Atropina/farmacologia , Callithrix , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Feminino , Interneurônios/efeitos dos fármacos , Masculino , Mecamilamina/farmacologia , Camundongos , Antagonistas Muscarínicos/farmacologia , Antagonistas Nicotínicos/farmacologia , Nociceptividade/efeitos dos fármacos , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley
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