| 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. | |
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MedLine Citation:
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PMID: 22753086 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. |
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Authors:
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Mario Roberto Senger; Lucas da Costa Andrade Gomes; Sabrina Baptista Ferreira; Carlos Roland Kaiser; Vitor Francisco Ferreira; Floriano Paes Silva |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-6-29 |
Journal Detail:
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Title: Chembiochem : a European journal of chemical biology Volume: - ISSN: 1439-7633 ISO Abbreviation: - Publication Date: 2012 Jun |
Date Detail:
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Created Date: 2012-7-3 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100937360 Medline TA: Chembiochem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. |
Affiliation:
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Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Bioquímica de Proteínas e Peptídeos, 21040-360 (Brazil). |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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