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1.
J Pharmacol Exp Ther ; 367(1): 147-154, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30076263

RESUMO

Myeloperoxidase (MPO) is a leukocyte-derived redox enzyme that has been linked to oxidative stress and damage in many inflammatory states, including cardiovascular disease. We have discovered aminopyridines that are potent mechanism-based inhibitors of MPO, with significant selectivity over the closely related thyroid peroxidase. 1-((6-Aminopyridin-3-yl)methyl)-3-(4-bromophenyl)urea (Aminopyridine 2) inhibited MPO in human plasma and blocked MPO-dependent vasomotor dysfunction ex vivo in rat aortic rings. Aminopyridine 2 also showed high oral bioavailability and inhibited MPO activity in vivo in a mouse model of peritonitis. Aminopyridine 2 could effectively be administered as a food admixture, making it an important tool for assessing the relative importance of MPO in preclinical models of chronic inflammatory disease.


Assuntos
Aminopiridinas/farmacologia , Inibidores Enzimáticos/farmacologia , Peroxidase/antagonistas & inibidores , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Disponibilidade Biológica , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley
2.
J Biomol Screen ; 18(3): 237-46, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23207740

RESUMO

Infection with human rhinovirus (HRV) is thought to result in acute respiratory exacerbations of chronic obstructive pulmonary disorder (COPD). Consequently, prevention of HRV infection may provide therapeutic benefit to these patients. As all major group HRV serotypes infect cells via an interaction between viral coat proteins and intercellular adhesion molecule-1 (ICAM-1), it is likely that inhibitors of this interaction would prevent or reduce infections. Our objective was to use phage display technology in conjunction with naive human antibody libraries to identify anti-ICAM-1 antibodies capable of functional blockade of HRV infection. Key to success was the development of a robust, functionally relevant high-throughput screen (HTS) compatible with the specific challenges of antibody screening. In this article, we describe the development of a novel homogeneous time-resolved fluorescence (HTRF) assay based on the inhibition of soluble ICAM-1 binding to live HRV16. We describe the implementation of the method in an antibody screening campaign and demonstrate the biological relevance of the assay by confirming the activity of resultant antibodies in a cell-based in vitro HRV infection assay.


Assuntos
Ensaios de Triagem em Larga Escala/métodos , Infecções por Picornaviridae/imunologia , Rhinovirus/imunologia , Anticorpos/imunologia , Anticorpos/metabolismo , Linhagem Celular Tumoral , Fluorescência , Células HeLa , Humanos , Molécula 1 de Adesão Intercelular/imunologia , Molécula 1 de Adesão Intercelular/metabolismo , Infecções por Picornaviridae/metabolismo , Rhinovirus/metabolismo
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