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1.
Biosci Biotechnol Biochem ; 78(5): 832-8, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25035986

RESUMO

The peptidyl prolyl cis/trans isomerase Pin1 enhances the uptake of triglycerides and the differentiation of fibroblasts into adipose cells in response to insulin stimulation. Pin1 downregulation could be a potential approach to prevent and treat obesity-related disorders. In order to identify an inhibitor of Pin1 that exhibited minimal cytotoxicity, we established a high-throughput screen for Pin1 inhibitors and used this method to identify an inhibitor from 1,056 crude fractions of two natural product libraries. The candidate, a phlorotannin called 974-B, was isolated from the seaweed, Ecklonia kurome. 974-B inhibited the differentiation of mouse embryonic fibroblasts and 3T3-L1 cells into adipose cells without inducing cytotoxicity. We discovered the Pin1 inhibitor, 974-B, from the seaweed, E. kurome, and showed that it blocks the differentiation of fibroblasts into adipose cells, suggesting that 974-B could be a lead drug candidate for obesity-related disorders.


Assuntos
Adipócitos/citologia , Diferenciação Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Ensaios de Triagem em Larga Escala , Peptidilprolil Isomerase/antagonistas & inibidores , Polifenóis/farmacologia , Alga Marinha/química , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Animais , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/isolamento & purificação , Fibroblastos/citologia , Camundongos , Peptidilprolil Isomerase de Interação com NIMA , Polifenóis/isolamento & purificação
2.
Biochem Biophys Res Commun ; 406(3): 439-43, 2011 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-21333629

RESUMO

Pin1, a peptidyl prolyl cis/trans isomerase (PPIase), is a potential target molecule for cancer, infectious disease, and Alzheimer's disease. We established a high-throughput screening method for Pin1 inhibitors, which employs a real-time fluorescence detector. This screening method identified 66 compounds that inhibit Pin1 out of 9756 compounds from structurally diverse chemical libraries. Further evaluations of surface plasmon resonance methods and a cell proliferation assay were performed. We discovered a cell-active inhibitor, TME-001 (2-(3-chloro-4-fluoro-phenyl)-isothiazol-3-one). Surprisingly, kinetic analyses revealed that TME-001 is the first compound that exhibits dual inhibition of Pin1 (IC50=6.1 µM) and cyclophilin, another type of PPIase, (IC50=13.7 µM). This compound does not inhibit FKBP. This finding suggests the existence of similarities of structure and reaction mechanism between Pin1 and cyclophilin, and may lead to a more complete understanding of the active sites of PPIases.


Assuntos
Antineoplásicos/farmacologia , Ciclofilinas/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Peptidilprolil Isomerase/antagonistas & inibidores , Tiazóis/farmacologia , Antineoplásicos/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Fluorescência , Células HeLa , Ensaios de Triagem em Larga Escala , Humanos , Peptidilprolil Isomerase de Interação com NIMA , Proteínas de Ligação a Tacrolimo/antagonistas & inibidores , Tiazóis/química , Tiazóis/isolamento & purificação
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