Premium
UDP‐GlcNAc Analogues as Inhibitors of O ‐GlcNAc Transferase (OGT): Spectroscopic, Computational, and Biological Studies
Author(s) -
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
Publication year - 2018
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201801083
Subject(s) - chemistry , moiety , ring (chemistry) , stereochemistry , affinities , binding affinities , alkyl , transferase , organic chemistry , enzyme , biochemistry , receptor
A series of glycomimetics of UDP‐GlcNAc, in which the β‐phosphate has been replaced by either an alkyl chain or a triazolyl ring and the sugar moiety has been replaced by a pyrrolidine ring, has been synthesized by the application of different click‐chemistry procedures.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.