| Author | Senger, Mario Roberto | |
| Author | Gomes, Lucas da Costa Andrade | |
| Author | Ferreira, Sabrina Baptista | |
| Author | Kaiser, Carlos Roland | |
| Author | Ferreira, Vitor Francisco | |
| Author | Silva, Floriano Paes | |
| Access date | 2017-09-19T16:25:12Z | |
| Available date | 2017-09-19T16:25:12Z | |
| Document date | 2012 | |
| Citation | SENGER, Mario Roberto; et al. Kinetics Studies on the Inhibition Mechanism of Pancreatic a-Amylase by Glycoconjugated 1H-1,2,3-Triazoles: A New Class of Inhibitors with Hypoglycemiant Activity. ChemBioChem , v.13, p.1584 – 1593, 2012. | pt_BR |
| ISSN | 1439-4227 | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/21062 | |
| Language | eng | pt_BR |
| Publisher | Wiley | pt_BR |
| Rights | restricted access | pt_BR |
| Subject in Portuguese | Estudos cinéticos | pt_BR |
| Subject in Portuguese | Inibidores da glicosidase | pt_BR |
| Subject in Portuguese | 1H-1,2,3-triazoles glicoconizados | pt_BR |
| Subject in Portuguese | Atividade hipoglicemiante | pt_BR |
| Subject in Portuguese | α-amylase panceática | pt_BR |
| Title | Kinetics studies on the inhibition mechanism of pancreatic α-amylase by glycoconjugated 1H-1,2,3-triazoles: a new class of inhibitors with hypoglycemiant activity | pt_BR |
| Type | Article | pt_BR |
| DOI | 10.1002/cbic.201200272 | |
| Abstract | Glycoconjugated 1H-1,2,3-triazoles (GCTs) comprise a new class of glycosidase inhibitors that are under investigation as promising therapeutic agents for a variety of diseases, including type 2 diabetes mellitus. However, few kinetics studies have been performed to clarify the mode of inhibition of GCTs with their target glycosidases. Our group has previously shown that some methyl-β-D-ribofuranosyl-1H-1,2,3-triazoles that inhibit baker's yeast maltase were also able to reduce post-prandial glucose levels in normal rats. We hypothesized that this hypoglycemiant activity was attributable to inhibition of mammalian α-glucosidases involved in sugar metabolism, such as pancreatic α-amylase. Hence, the aim of this work was to test a series of 26 GCTs on porcine pancreatic α-amylase (PPA) and to characterize their inhibition mechanisms. Six GCTs, all ribofuranosyl-derived GCTs, significantly inhibited PPA, with IC(50) values in the middle to high micromolar range. Our results also demonstrated that ribofuranosyl-derived GCTs are reversible, noncompetitive inhibitors when using 2-chloro-4-nitrophenyl-α-D-maltotrioside as a substrate. E/ES affinity ratios (α) ranged from 0.3 to 1.1, with the majority of ribofuranosyl-derived GCTs preferentially forming stable ternary ESI complexes. Competition assays with acarbose showed that ribofuranosyl-derived GCTs bind to PPA in a mutually exclusive fashion. The data presented here show that pancreatic α-amylase is one of the possible molecular targets in the pharmacological activity of ribofuranosyl-derived GCTs. Our results also provide important mechanistic insight that can be of major help to develop this new class of synthetic small molecules into more potent compounds with anti-diabetic activity through rational drug design. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Proteínas e Peptídeos. Rio de Janeiro, RJ. Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Proteínas e Peptídeos. Rio de Janeiro, RJ. Brasil. | pt_BR |
| Affilliation | Universidade Federal do Rio de Janeiro. Instituto de Química. Campus Macaé. Macaé, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal do Rio de Janeiro. Instituto de Química. Departamento de Química Orgânica. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal Fluminense. Instituto de Química. Departamento de Química Orgânica. Campus do Valonguinho. NIterói, RJ, Brasil | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Proteínas e Peptídeos. Rio de Janeiro, RJ. Brasil. | pt_BR |
| Subject | Glycoconjugated 1H-1,2,3-triazoles | pt_BR |
| Subject | Hypoglycemiant Activity | pt_BR |
| Subject | Kinetics Studies | pt_BR |
| Subject | glycosidase inhibitors | pt_BR |
| Subject | pancreatic α-amylase | pt_BR |
| e-ISSN | 1439-7633 | |
| Embargo date | 2030-01-01 | |
