Potent Glycosidase Inhibition with Heterovalent Fullerenes: Unveiling the Binding Modes Triggering Multivalent Inhibition

Marta Abellán Flos, M. Isabel García Moreno, Carmen Ortiz Mellet, Jose Manuel García Fernández, Jean Francois Nierengarten, Stéphane P. Vincent

Research output: Contribution to journalArticle

Abstract

Glycosidases are key enzymes in metabolism, pathogenic/antipathogenic mechanisms and normal cellular functions. Recently, a novel approach for glycosidase inhibition that conveys multivalent glycomimetic conjugates has emerged. Many questions regarding the mechanism(s) of multivalent enzyme inhibition remain unanswered. Herein we report the synthesis of a collection of novel homo- and heterovalent glyco(mimetic)-fullerenes purposely conceived for probing the contribution of non-catalytic pockets in glysosidases to the multivalent inhibitory effect. Their affinities towards selected glycosidases were compared with data from homovalent fullerene conjugates. An original competitive glycosidase–lectin binding assay demonstrated that the multivalent derivatives and the substrate compete for low affinity non-glycone binding sites of the enzyme, leading to inhibition by a “recognition and blockage” mechanism. Most notably, this work provides evidence for enzyme inhibition by multivalent glycosystems, which will likely have a strong impact in the glycosciences given the utmost relevance of multivalency in Nature.

Original languageEnglish
Pages (from-to)11450-11460
Number of pages11
JournalChemistry: A European Journal
Volume22
Issue number32
DOIs
Publication statusPublished - 2016

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Keywords

  • binding modes
  • fullerenes
  • glycosidases
  • heterovalency
  • inhibitors

Cite this

Abellán Flos, M., García Moreno, M. I., Ortiz Mellet, C., García Fernández, J. M., Nierengarten, J. F., & Vincent, S. P. (2016). Potent Glycosidase Inhibition with Heterovalent Fullerenes: Unveiling the Binding Modes Triggering Multivalent Inhibition. Chemistry: A European Journal, 22(32), 11450-11460. https://doi.org/10.1002/chem.201601673