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 journalArticle

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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A series of glycomimetics of UDP-GlcNAc, in which the β-phosphate has been replaced by either an alkyl chain or a triazolyl ring and the sugar moiety has been replaced by a pyrrolidine ring, has been synthesized by the application of different click-chemistry procedures.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

Fingerprint

Uridine Diphosphate
Phosphates
Epitopes
Saturation (materials composition)
Carbohydrates
Sugars
Nuclear magnetic resonance spectroscopy
Ligands
O-GlcNAc transferase

Keywords

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

Cite this

Ghirardello, M., Perrone, D., Chinaglia, N., Sádaba, D., Delso, I., Tejero, T., ... Merino, P. (2018). UDP-GlcNAc Analogues as Inhibitors of O-GlcNAc Transferase (OGT): Spectroscopic, Computational, and Biological Studies. Chemistry: a European Journal, 24(28), 7264-7272. https://doi.org/10.1002/chem.201801083
Ghirardello, Mattia ; Perrone, Daniela ; Chinaglia, Nicola ; Sádaba, David ; Delso, Ignacio ; Tejero, Tomas ; Marchesi, Elena ; Fogagnolo, Marco ; Rafie, Karim ; van Aalten, Daan M F ; Merino, Pedro. / UDP-GlcNAc Analogues as Inhibitors of O-GlcNAc Transferase (OGT) : Spectroscopic, Computational, and Biological Studies. In: Chemistry: a European Journal. 2018 ; Vol. 24, No. 28. pp. 7264-7272.
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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.",
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Ghirardello, M, Perrone, D, Chinaglia, N, Sádaba, D, Delso, I, Tejero, T, Marchesi, E, Fogagnolo, M, Rafie, K, van Aalten, DMF & Merino, P 2018, 'UDP-GlcNAc Analogues as Inhibitors of O-GlcNAc Transferase (OGT): Spectroscopic, Computational, and Biological Studies', Chemistry: a European Journal, vol. 24, no. 28, pp. 7264-7272. https://doi.org/10.1002/chem.201801083

UDP-GlcNAc Analogues as Inhibitors of O-GlcNAc Transferase (OGT) : Spectroscopic, Computational, and Biological Studies. / Ghirardello, Mattia; Perrone, Daniela; Chinaglia, Nicola; Sádaba, David; Delso, Ignacio; Tejero, Tomas; Marchesi, Elena; Fogagnolo, Marco; Rafie, Karim; van Aalten, Daan M F; Merino, Pedro.

In: Chemistry: a European Journal, Vol. 24, No. 28, 17.05.2018, p. 7264-7272.

Research output: Contribution to journalArticle

TY - JOUR

T1 - UDP-GlcNAc Analogues as Inhibitors of O-GlcNAc Transferase (OGT)

T2 - Spectroscopic, Computational, and Biological Studies

AU - Ghirardello, Mattia

AU - Perrone, Daniela

AU - Chinaglia, Nicola

AU - Sádaba, David

AU - Delso, Ignacio

AU - Tejero, Tomas

AU - Marchesi, Elena

AU - Fogagnolo, Marco

AU - Rafie, Karim

AU - van Aalten, Daan M F

AU - Merino, Pedro

N1 - Ministerio de Economía y Competitividad. Grant Number: CTQ2016-76155-R; Wellcome Trust. Grant Number: 110061

PY - 2018/5/17

Y1 - 2018/5/17

N2 - 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.

AB - 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.

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KW - carbohydrates

KW - glycosylation

KW - glycosyltransferases

KW - nucleotide diphosphate analogues

KW - Biological Evolution

KW - Magnetic Resonance Spectroscopy

KW - Computer Simulation

KW - Humans

KW - Ligands

KW - N-Acetylglucosaminyltransferases/chemistry

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U2 - 10.1002/chem.201801083

DO - 10.1002/chem.201801083

M3 - Article

C2 - 29513364

VL - 24

SP - 7264

EP - 7272

JO - Chemistry: a European Journal

JF - Chemistry: a European Journal

SN - 0947-6539

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