UDP-GlcNAc Analogues as Inhibitors of O-GlcNAc Transferase (OGT): Spectroscopic, Computational, and Biological Studies

Mattia Ghirardello, Daniela Perrone, Nicola Chinaglia, David Sádaba, Ignacio Delso, Tomas Tejero, Elena Marchesi, Marco Fogagnolo, Karim Rafie, Daan M F van Aalten, Pedro Merino

    Research output: Contribution to journalArticlepeer-review

    8 Citations (Scopus)
    209 Downloads (Pure)

    Abstract

    A series of glycomimetics of UDP-GlcNAc, in which the β-phosphate has been replaced by either an alkyl chain or a triazolyl ring and the sugar moiety has been replaced by a pyrrolidine ring, has been synthesized by the application of different click-chemistry procedures. Their affinities for human O-GlcNAc transferase (hOGT) have been evaluated and studied both spectroscopically and computationally. The binding epitopes of the best ligands have been determined in solution by means of saturation transfer difference (STD) NMR spectroscopy. Experimental, spectroscopic, and computational results are in agreement, pointing out the essential role of the binding of β-phosphate. We have found that the loss of interactions from the β-phosphate can be counterbalanced by the presence of hydrophobic groups at a pyrroline ring acting as a surrogate of the carbohydrate unit. Two of the prepared glycomimetics show inhibition at a micromolar level.

    Original languageEnglish
    Pages (from-to)7264-7272
    Number of pages9
    JournalChemistry: a European Journal
    Volume24
    Issue number28
    Early online date7 Mar 2018
    DOIs
    Publication statusPublished - 17 May 2018

    Keywords

    • bioconjugates
    • carbohydrates
    • glycosylation
    • glycosyltransferases
    • nucleotide diphosphate analogues
    • Biological Evolution
    • Magnetic Resonance Spectroscopy
    • Computer Simulation
    • Humans
    • Ligands
    • N-Acetylglucosaminyltransferases/chemistry

    ASJC Scopus subject areas

    • General Chemistry

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