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1.
EMBO J ; 31(18): 3655-66, 2012 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-22863780

RESUMO

Most common genetic factors known to cause intellectual disability are Down syndrome and Fragile X syndrome. However, the underlying cellular and molecular mechanisms of intellectual disability remain unclear. Recently, dendritic spine dysmorphogenesis and impaired local protein synthesis are posited to contribute to the cellular mechanisms of intellectual disability. Here, we show that Down syndrome critical region1 (DSCR1) interacts with Fragile X mental retardation protein (FMRP) and regulates both dendritic spine morphogenesis and local protein synthesis. Interestingly, decreasing the level of FMRP restores the DSCR1-induced changes in dendritic spine morphology. Our results imply that DSCR1 is a novel regulator of FMRP and that Fragile X syndrome and Down syndrome may share disturbances in common pathways that regulate dendritic spine morphology and local protein synthesis.


Assuntos
Espinhas Dendríticas/metabolismo , Proteína do X Frágil da Deficiência Intelectual/fisiologia , Regulação da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Proteínas Musculares/fisiologia , Animais , Região CA1 Hipocampal , Proteínas de Ligação ao Cálcio , Proteínas de Ligação a DNA , Síndrome de Down/genética , Síndrome de Down/metabolismo , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/metabolismo , Células HEK293 , Humanos , Processamento de Imagem Assistida por Computador , Imageamento Tridimensional/métodos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Morfogênese , Proteínas Musculares/metabolismo , Neurônios/metabolismo , Fosforilação , RNA Interferente Pequeno/metabolismo
2.
Antimicrob Agents Chemother ; 58(1): 419-23, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24189245

RESUMO

GSK1322322 is a potent peptide deformylase inhibitor with in vitro and in vivo activity against multidrug-resistant skin and respiratory pathogens. This report provides plasma and intrapulmonary pharmacokinetics, safety, and tolerability of GSK1322322 after repeat (twice daily intravenous dosing for 4 days) dosing at 1,500 mg. Plasma samples were collected over the last 12-hour dosing interval of repeat dosing following the day 4 morning dose (the last dose). Bronchoalveolar lavage samples were collected once in each subject, either before or at 2 or 6 h after the last intravenous dose. Plasma area under the concentration-time curve (AUC0-τ) was 66.7 µg · h/ml, and maximum concentration of drug in serum (Cmax) was 25.4 µg/ml following repeat doses of intravenous GSK1322322. The time course of epithelial lining fluid (ELF) and alveolar macrophages (AM) mirrored the plasma concentration-time profile. The AUC0-τ for ELF and AM were 78.9 µg · h/ml and 169 µg · h/ml, respectively. The AUC0-τ ratios of ELF and AM to total plasma were 1.2 and 2.5, respectively. These ratios increased to 3.5 and 7.4, respectively, when unbound plasma was considered. These results are supportive of GSK1322322 as a potential antimicrobial agent for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens. (This study has been registered at ClinicalTrials.gov under registration number NCT01610388.).


Assuntos
Antibacterianos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Ácidos Hidroxâmicos/uso terapêutico , Macrófagos Alveolares/metabolismo , Adulto , Antibacterianos/farmacocinética , Área Sob a Curva , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Lavagem Broncoalveolar , Feminino , Humanos , Ácidos Hidroxâmicos/farmacocinética , Masculino , Pessoa de Meia-Idade , Infecções Respiratórias , Adulto Jovem
3.
Antimicrob Agents Chemother ; 58(11): 6518-27, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25136015

RESUMO

GSK1322322 represents a new class of antibiotics that targets an essential bacterial enzyme required for protein maturation, peptide deformylase. This multicenter, randomized, phase IIa study compared the safety, tolerability, and efficacy of GSK1322322 at 1,500 mg twice daily (b.i.d.) with that of linezolid at 600 mg b.i.d. in patients suspected of having Gram-positive acute bacterial skin and skin structure infections (ABSSSIs). The primary endpoint was assessment of the safety of GSK1322322, and a key secondary endpoint was the number of subjects with a ≥20% decrease in lesion area from the baseline at 48 and 72 h after treatment initiation. GSK1322322 administration was associated with mild-to-moderate drug-related adverse events, most commonly, nausea, vomiting, diarrhea, and headache. Adverse events (86% versus 74%) and withdrawals (28% versus 11%) were more frequent in the GSK1322322-treated group. Treatment with GSK1322322 and linezolid was associated with ≥20% decreases from the baseline in the lesion area in 73% (36/49) and 92% (24/26) of the patients, respectively, at the 48-h assessment and in 96% (44/46) and 100% (25/25) of the patients, respectively, at the 72-h assessment. Reductions in exudate/pus, pain, and skin infection scores were comparable between the GSK1322322 and linezolid treatments. The clinical success rates within the intent-to-treat population and the per-protocol population that completed this study were 67 and 91%, respectively, in the GSK1322322-treated group and 89 and 100%, respectively, in the linezolid-treated group. These results will be used to guide dose selection in future studies with GSK1322322 to optimize its tolerability and efficacy in patients with ABSSSIs. (This study has been registered at ClinicalTrials.gov under registration no. NCT01209078 and at http://www.gsk-clinicalstudyregister.com [PDF113414].).


Assuntos
Antibacterianos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Ácidos Hidroxâmicos/efeitos adversos , Ácidos Hidroxâmicos/uso terapêutico , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Infecções Cutâneas Estafilocócicas/tratamento farmacológico , Acetamidas/efeitos adversos , Acetamidas/uso terapêutico , Adulto , Amidoidrolases/antagonistas & inibidores , Antibacterianos/efeitos adversos , Citocromo P-450 CYP3A/efeitos dos fármacos , Inibidores do Citocromo P-450 CYP3A , Farmacorresistência Bacteriana Múltipla , Feminino , Humanos , Linezolida , Masculino , Oxazolidinonas/efeitos adversos , Oxazolidinonas/uso terapêutico , Infecções Cutâneas Estafilocócicas/microbiologia , Resultado do Tratamento , beta-Lactamases/biossíntese
4.
Biochemistry ; 50(9): 1524-34, 2011 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-21235238

RESUMO

The interactions of chemokines with their G protein-coupled receptors play critical roles in the control of leukocyte trafficking in normal homeostasis and in inflammatory responses. Tyrosine sulfation is a common post-translational modification in the amino-terminal regions of chemokine receptors. However, tyrosine sulfation of chemokine receptors is commonly incomplete or heterogeneous. To investigate the possibility that differential sulfation of two adjacent tyrosine residues could bias the responses of chemokine receptor CCR3 to different chemokines, we have studied the binding of three chemokines (eotaxin-1/CCL11, eotaxin-2/CCL24, and eotaxin-3/CCL26) to an N-terminal CCR3-derived peptide in each of its four possible sulfation states. Whereas the nonsulfated peptide binds to the three chemokines with approximately equal affinity, sulfation of Tyr-16 gives rise to 9-16-fold selectivity for eotaxin-1 over the other two chemokines. Subsequent sulfation of Tyr-17 contributes additively to the affinity for eotaxin-1 and eotaxin-2 but cooperatively to the affinity for eotaxin-3. The doubly sulfated peptide selectively binds to both eotaxin-1 and eotaxin-3 approximately 10-fold more tightly than to eotaxin-2. Nuclear magnetic resonance chemical shift mapping indicates that these variations in affinity probably result from only subtle differences in the chemokine surfaces interacting with these receptor peptides. These data support the proposal that variations in sulfation states or levels may regulate the responsiveness of chemokine receptors to their cognate chemokines.


Assuntos
Quimiocinas CC/metabolismo , Quimiocinas/metabolismo , Fragmentos de Peptídeos/metabolismo , Receptores CCR3/química , Tirosina/metabolismo , Quimiocinas CC/química , Fragmentos de Peptídeos/química , Ligação Proteica , Receptores CCR3/metabolismo , Sulfatos/química , Sulfatos/metabolismo , Tirosina/química
5.
Chem Biol ; 16(2): 153-61, 2009 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-19246006

RESUMO

Sulfation of tyrosine is a common posttranslational modification of secreted proteins that influences numerous physiological and pathological processes. Studies of tyrosine sulfation have been hindered by the difficulty of introducing sulfate groups at specific positions of peptides and proteins. Here we report a general strategy for synthesis of peptides containing sulfotyrosine at one or more specific position(s). The approach provides a substantial improvement in both yield and convenience over existing methods. Using synthetic sulfopeptides derived from the chemokine receptor CCR3, we demonstrate that sulfation enhances affinity for the chemokine eotaxin by approximately 7-fold or more than 28-fold, depending on which of two adjacent tyrosine residues is sulfated. The synthetic methodology will substantially enhance efforts to understand the functional and structural consequences of protein tyrosine sulfation.


Assuntos
Quimiocina CCL11/metabolismo , Peptídeos/síntese química , Peptídeos/metabolismo , Tirosina/análogos & derivados , Sítios de Ligação , Peptídeos/química , Ligação Proteica , Receptores CCR3/química , Receptores CCR3/metabolismo , Tirosina/síntese química
6.
N Biotechnol ; 25(5): 299-317, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19658209

RESUMO

The post-translational sulfation of tyrosine residues occurs in numerous secreted and integral membrane proteins and, in many cases, plays a crucial role in controlling the interactions of these proteins with physiological binding partners as well as invading pathogens. Recent advances in our understanding of protein tyrosine sulfation have come about owing to the cloning of two human tyrosylprotein sulfotransferases (TPST-1 and TPST-2), the development of novel analytical and synthetic methodologies and detailed studies of proteins and peptides containing sulfotyrosine residues. In this article, we describe the TPST enzymes, review the major techniques available for studying the presence, location and function of tyrosine sulfation in proteins and discuss the biological functions and biochemical interactions of several proteins (or protein families) in which tyrosine sulfation influences the protein function. In particular, we describe the detailed evidence supporting the importance of tyrosine sulfation in the cellular adhesion function of P-selectin glycoprotein ligand-1, the leukocyte trafficking and pathogen invasion functions of chemokine receptors and the ligand binding and activation of other G-protein-coupled receptors by complement proteins, phospholipdis and glycoprotein hormones.


Assuntos
Processamento de Proteína Pós-Traducional , Proteínas/metabolismo , Tirosina/química , Tirosina/metabolismo , Sequência de Aminoácidos , Animais , Domínio Catalítico , Sequência Consenso , Humanos , Proteínas de Membrana/química , Proteínas de Membrana/genética , Dados de Sequência Molecular , Estrutura Molecular , Estrutura Terciária de Proteína , Homologia de Sequência de Aminoácidos , Sulfotransferases/química , Sulfotransferases/genética
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