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1.
PLoS One ; 7(5): e36833, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22666328

RESUMO

Fusion between the viral and target cell membranes is an obligatory step for the infectivity of all enveloped virus, and blocking this process is a clinically validated therapeutic strategy.Viral fusion is driven by specialized proteins which, although specific to each virus, act through a common mechanism, the formation of a complex between two heptad repeat (HR) regions. The HR regions are initially separated in an intermediate termed "prehairpin", which bridges the viral and cell membranes, and then fold onto each other to form a 6-helical bundle (6HB), driving the two membranes to fuse. HR-derived peptides can inhibit viral infectivity by binding to the prehairpin intermediate and preventing its transition to the 6HB.The antiviral activity of HR-derived peptides differs considerably among enveloped viruses. For weak inhibitors, potency can be increased by peptide engineering strategies, but sequence-specific optimization is time-consuming. In seeking ways to increase potency without changing the native sequence, we previously reported that attachment to the HR peptide of a cholesterol group ("cholesterol-tagging") dramatically increases its antiviral potency, and simultaneously increases its half-life in vivo. We show here that antiviral potency may be increased by combining cholesterol-tagging with dimerization of the HR-derived sequence, using as examples human parainfluenza virus, Nipah virus, and HIV-1. Together, cholesterol-tagging and dimerization may represent strategies to boost HR peptide potency to levels that in some cases may be compatible with in vivo use, possibly contributing to emergency responses to outbreaks of existing or novel viruses.


Assuntos
Antivirais/química , Antivirais/farmacologia , Produtos Biológicos/química , Desenho de Fármacos , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Proteínas Virais de Fusão/química , Sequência de Aminoácidos , Animais , Antivirais/metabolismo , Colesterol/metabolismo , Cricetinae , Células HeLa , Humanos , Dados de Sequência Molecular , Fragmentos de Peptídeos/metabolismo , Multimerização Proteica , Estrutura Terciária de Proteína , Vírus de RNA/efeitos dos fármacos , Vírus de RNA/fisiologia , Replicação Viral/efeitos dos fármacos
2.
J Pept Sci ; 17(4): 270-80, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21294225

RESUMO

Obesity is one of the major risk factors for type 2 diabetes, and the development of agents, that can simultaneously achieve glucose control and weight loss, is being actively pursued. Therapies based on peptide mimetics of the gut hormone glucagon-like peptide 1 (GLP-1) are rapidly gaining favor, due to their ability to increase insulin secretion in a strictly glucose-dependent manner, with little or no risk of hypoglycemia, and to their additional benefit of causing a modest, but durable weight loss. Oxyntomodulin (OXM), a 37-amino acid peptide hormone of the glucagon (GCG) family with dual agonistic activity on both the GLP-1 (GLP1R) and the GCG (GCGR) receptors, has been shown to reduce food intake and body weight in humans, with a lower incidence of treatment-associated nausea than GLP-1 mimetics. As for other peptide hormones, its clinical application is limited by the short circulatory half-life, a major component of which is cleavage by the enzyme dipeptidyl peptidase IV (DPP-IV). SAR studies on OXM, described herein, led to the identification of molecules resistant to DPP-IV degradation, with increased potency as compared to the natural hormone. Analogs derivatized with a cholesterol moiety display increased duration of action in vivo. Moreover, we identified a single substitution which can change the OXM pharmacological profile from a dual GLP1R/GCGR agonist to a selective GLP1R agonist. The latter finding enabled studies, described in detail in a separate study (Pocai A, Carrington PE, Adams JR, Wright M, Eiermann G, Zhu L, Du X, Petrov A, Lassman ME, Jiang G, Liu F, Miller C, Tota LM, Zhou G, Zhang X, Sountis MM, Santoprete A, Capitò E, Chicchi GG, Thornberry N, Bianchi E, Pessi A, Marsh DJ, SinhaRoy R. Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice. Diabetes 2009; 58: 2258-2266), which highlight the potential of GLP1R/GCGR dual agonists as a potentially superior class of therapeutics over the pure GLP1R agonists currently in clinical use.


Assuntos
Dipeptidil Peptidase 4/metabolismo , Oxintomodulina/química , Oxintomodulina/metabolismo , Sequência de Aminoácidos , Animais , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Camundongos , Dados de Sequência Molecular , Estrutura Molecular , Obesidade/tratamento farmacológico , Oxintomodulina/farmacologia , Oxintomodulina/uso terapêutico , Peptídeos/síntese química , Peptídeos/química , Peptídeos/genética , Redução de Peso/efeitos dos fármacos
3.
Bioorg Med Chem ; 18(24): 8669-78, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21115285

RESUMO

Reverse cholesterol transport promoted by HDL-apoA-I is an important mechanism of protection against atherosclerosis. We have previously identified apoA-I mimetic peptides by synthesizing analogs of the 22 amino acid apoA-I consensus sequence (apoA-I(cons)) containing non-natural aliphatic amino acids. Here we examined the effect of different aliphatic non-natural amino acids on the structure-activity relationship (SAR) of apoA-I mimetic peptides. These novel apoA-I mimetics, with long hydrocarbon chain (C(5-8)) amino acids incorporated in the amphipathic α helix of the apoA-I(cons), have the following properties: (i) they stimulate in vitro cholesterol efflux from macrophages via ABCA1; (ii) they associate with HDL and cause formation of pre-ß HDL particles when incubated with human and mouse plasma; (iii) they associate with HDL and induce pre-ß HDL formation in vivo, with a corresponding increase in ABCA1-dependent cholesterol efflux capacity ex vivo; (iv) at high dose they associate with VLDL and induce hypertriglyceridemia in mice. These results suggest our peptide design confers activities that are potentially anti-atherogenic. However a dosing regimen which maximizes their therapeutic properties while minimizing adverse effects needs to be established.


Assuntos
Apolipoproteína A-I/química , Lipoproteínas de Alta Densidade Pré-beta/biossíntese , Lipoproteínas HDL/efeitos dos fármacos , Fragmentos de Peptídeos/química , Triglicerídeos/biossíntese , Animais , Lipoproteínas de Alta Densidade Pré-beta/efeitos dos fármacos , Humanos , Lipoproteínas HDL/metabolismo , Camundongos , Mimetismo Molecular , Fragmentos de Peptídeos/farmacologia , Relação Estrutura-Atividade , Triglicerídeos/metabolismo
4.
Diabetes ; 58(10): 2258-66, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19602537

RESUMO

OBJECTIVE: Oxyntomodulin (OXM) is a glucagon-like peptide 1 (GLP-1) receptor (GLP1R)/glucagon receptor (GCGR) dual agonist peptide that reduces body weight in obese subjects through increased energy expenditure and decreased energy intake. The metabolic effects of OXM have been attributed primarily to GLP1R agonism. We examined whether a long acting GLP1R/GCGR dual agonist peptide exerts metabolic effects in diet-induced obese mice that are distinct from those obtained with a GLP1R-selective agonist. RESEARCH DESIGN AND METHODS: We developed a protease-resistant dual GLP1R/GCGR agonist, DualAG, and a corresponding GLP1R-selective agonist, GLPAG, matched for GLP1R agonist potency and pharmacokinetics. The metabolic effects of these two peptides with respect to weight loss, caloric reduction, glucose control, and lipid lowering, were compared upon chronic dosing in diet-induced obese (DIO) mice. Acute studies in DIO mice revealed metabolic pathways that were modulated independent of weight loss. Studies in Glp1r(-/-) and Gcgr(-/-) mice enabled delineation of the contribution of GLP1R versus GCGR activation to the pharmacology of DualAG. RESULTS: Peptide DualAG exhibits superior weight loss, lipid-lowering activity, and antihyperglycemic efficacy comparable to GLPAG. Improvements in plasma metabolic parameters including insulin, leptin, and adiponectin were more pronounced upon chronic treatment with DualAG than with GLPAG. Dual receptor agonism also increased fatty acid oxidation and reduced hepatic steatosis in DIO mice. The antiobesity effects of DualAG require activation of both GLP1R and GCGR. CONCLUSIONS: Sustained GLP1R/GCGR dual agonism reverses obesity in DIO mice and is a novel therapeutic approach to the treatment of obesity.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/farmacologia , Obesidade/prevenção & controle , Oxintomodulina/uso terapêutico , Receptores de Glucagon/agonistas , Sequência de Aminoácidos , Animais , Peso Corporal/efeitos dos fármacos , Células CHO/efeitos dos fármacos , Cricetinae , Cricetulus , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/prevenção & controle , Gorduras na Dieta/farmacologia , Ingestão de Energia , Peptídeo 1 Semelhante ao Glucagon/agonistas , Peptídeo 1 Semelhante ao Glucagon/genética , Receptor do Peptídeo Semelhante ao Glucagon 1 , Injeções Subcutâneas , Insulina/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Obesidade/induzido quimicamente , Obesidade/complicações , Oxintomodulina/administração & dosagem , Receptores de Glucagon/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Redução de Peso/efeitos dos fármacos
5.
Bioorg Med Chem Lett ; 19(3): 633-8, 2009 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-19109015

RESUMO

We report a new series of inhibitors for hepatitis C virus NS5B RNA polymerase containing a constrained pentacyclic scaffold. Our SAR studies led to the identification of hexahydroindolo[2,1-a]pyrrolo[3,2-d][2]benzazepines exposing basic groups. The compounds displayed a high activity in the enzyme assay and displayed good activity in the cell-based (replicon) assay in the presence of serum proteins.


Assuntos
Química Farmacêutica/métodos , Desenho de Fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Benzazepinas/química , RNA Polimerases Dirigidas por DNA/química , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Fígado/efeitos dos fármacos , Fígado/virologia , Modelos Químicos , Modelos Moleculares , Conformação Molecular , RNA Viral/genética , Relação Estrutura-Atividade
6.
Chem Commun (Camb) ; (14): 1854-6, 2005 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-15795765

RESUMO

A C-H activating Pd-catalysed alkenylation of indole is regiospecific for 2-substitution when the nitrogen carries a 2-pyridylmethyl substituent.

7.
J Org Chem ; 69(24): 8525-8, 2004 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-15549836

RESUMO

A straightforward procedure for the regio- and stereoselective synthesis of alpha-hydrazino ketones is described. Manganese enolates and manganese enamines derived from ketones and from the corresponding N-sulfinylimines react with azodicarboxylate esters (DTBAD and DEAD) in a regioselective fashion to afford in good to excellent yields the kinetic alpha-hydrazino ketones as sole or highly prevalent products. When enantiopure N-sulfinyl manganese enamines were used the stereoselectivity of these reactions ranged from 40% to 68% ee.

8.
J Org Chem ; 69(23): 8168-71, 2004 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-15527316

RESUMO

A nitrogen-containing superbase such as TMG was found to be an effective catalyst for the reaction between N-diphenylphosphinoyl imines and nitroalkanes. Exploiting a protocol that avoids the use of any solvent also during workup procedure, we synthesized a series of beta-nitroamines in excellent yields and high diastereomeric ratios. These results, combined with the capability of the indium in conjunction with Zn as the stoichiometric reducing agent to perform in aqueous medium reduction of the nitro group under mild reaction conditions, led us to devise a three-step, one-pot synthesis of a range of 1,2-diamines, making use of environmentally friendly procedures in the various steps.

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