Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/21062
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
Authors: Senger, Mario Roberto
Gomes, Lucas da Costa Andrade
Ferreira, Sabrina Baptista
Kaiser, Carlos Roland
Ferreira, Vitor Francisco
Silva, Floriano Paes
Affilliation: Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Proteínas e Peptídeos. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Proteínas e Peptídeos. Rio de Janeiro, RJ. Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Química. Campus Macaé. Macaé, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Química. Departamento de Química Orgânica. Rio de Janeiro, RJ, Brasil.
Universidade Federal Fluminense. Instituto de Química. Departamento de Química Orgânica. Campus do Valonguinho. NIterói, RJ, Brasil
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Proteínas e Peptídeos. Rio de Janeiro, RJ. Brasil.
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.
Keywords: Glycoconjugated 1H-1,2,3-triazoles
Hypoglycemiant Activity
Kinetics Studies
glycosidase inhibitors
pancreatic α-amylase
keywords: Estudos cinéticos
Inibidores da glicosidase
1H-1,2,3-triazoles glicoconizados
Atividade hipoglicemiante
α-amylase panceática
Issue Date: 2012
Publisher: Wiley
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.
DOI: 10.1002/cbic.201200272
ISSN: 1439-4227
Copyright: restricted access
Appears in Collections:IOC - Artigos de Periódicos

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