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

A series of glycomimetics of UDP-GlcNAc, in which the ß-phosphate has been replaced by either an alkyl chain or a triazolyl ring and the sugar moiety has been replaced by a pyrrolidine ring, has been synthesized by the application of different click-chemistry procedures.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

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Autores: Ghirardello, M., Perrone, D., Chinaglia, N., Sádaba, D., Delso, I., Tejero, T., Marchesi, E., Fogagnolo, M., Rafie, K., van Aalten, D.M.F., Merino, P.
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2018
País:España
Institución:Universidad de Zaragoza
Repositorio:Zaguán. Repositorio Digital de la Universidad de Zaragoza
OAI Identifier:oai:zaguan.unizar.es:79330
Acceso en línea:http://zaguan.unizar.es/record/79330
Access Level:acceso abierto
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spelling UDP-GlcNAc Analogues as Inhibitors of O-GlcNAc Transferase (OGT): Spectroscopic, Computational, and Biological StudiesGhirardello, M.Perrone, D.Chinaglia, N.Sádaba, D.Delso, I.Tejero, T.Marchesi, E.Fogagnolo, M.Rafie, K.van Aalten, D.M.F.Merino, P.A series of glycomimetics of UDP-GlcNAc, in which the ß-phosphate has been replaced by either an alkyl chain or a triazolyl ring and the sugar moiety has been replaced by a pyrrolidine ring, has been synthesized by the application of different click-chemistry procedures.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 ß-phosphate. We have found that the loss of interactions from the ß-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.2018info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttp://zaguan.unizar.es/record/79330reponame:Zaguán. Repositorio Digital de la Universidad de Zaragozainstname:Universidad de ZaragozaInglésinfo:eu-repo/grantAgreement/ES/DGA/E10info:eu-repo/grantAgreement/ES/MINECO-FEDER/CTQ2016-76155-Rinfo:eu-repo/semantics/openAccessoai:zaguan.unizar.es:793302026-05-29T13:59:51Z
dc.title.none.fl_str_mv UDP-GlcNAc Analogues as Inhibitors of O-GlcNAc Transferase (OGT): Spectroscopic, Computational, and Biological Studies
title UDP-GlcNAc Analogues as Inhibitors of O-GlcNAc Transferase (OGT): Spectroscopic, Computational, and Biological Studies
spellingShingle UDP-GlcNAc Analogues as Inhibitors of O-GlcNAc Transferase (OGT): Spectroscopic, Computational, and Biological Studies
Ghirardello, M.
title_short UDP-GlcNAc Analogues as Inhibitors of O-GlcNAc Transferase (OGT): Spectroscopic, Computational, and Biological Studies
title_full UDP-GlcNAc Analogues as Inhibitors of O-GlcNAc Transferase (OGT): Spectroscopic, Computational, and Biological Studies
title_fullStr UDP-GlcNAc Analogues as Inhibitors of O-GlcNAc Transferase (OGT): Spectroscopic, Computational, and Biological Studies
title_full_unstemmed UDP-GlcNAc Analogues as Inhibitors of O-GlcNAc Transferase (OGT): Spectroscopic, Computational, and Biological Studies
title_sort UDP-GlcNAc Analogues as Inhibitors of O-GlcNAc Transferase (OGT): Spectroscopic, Computational, and Biological Studies
dc.creator.none.fl_str_mv Ghirardello, M.
Perrone, D.
Chinaglia, N.
Sádaba, D.
Delso, I.
Tejero, T.
Marchesi, E.
Fogagnolo, M.
Rafie, K.
van Aalten, D.M.F.
Merino, P.
author Ghirardello, M.
author_facet Ghirardello, M.
Perrone, D.
Chinaglia, N.
Sádaba, D.
Delso, I.
Tejero, T.
Marchesi, E.
Fogagnolo, M.
Rafie, K.
van Aalten, D.M.F.
Merino, P.
author_role author
author2 Perrone, D.
Chinaglia, N.
Sádaba, D.
Delso, I.
Tejero, T.
Marchesi, E.
Fogagnolo, M.
Rafie, K.
van Aalten, D.M.F.
Merino, P.
author2_role author
author
author
author
author
author
author
author
author
author
description A series of glycomimetics of UDP-GlcNAc, in which the ß-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 ß-phosphate. We have found that the loss of interactions from the ß-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.
publishDate 2018
dc.date.none.fl_str_mv 2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://zaguan.unizar.es/record/79330
url http://zaguan.unizar.es/record/79330
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/ES/DGA/E10
info:eu-repo/grantAgreement/ES/MINECO-FEDER/CTQ2016-76155-R
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv
publisher.none.fl_str_mv
dc.source.none.fl_str_mv reponame:Zaguán. Repositorio Digital de la Universidad de Zaragoza
instname:Universidad de Zaragoza
instname_str Universidad de Zaragoza
reponame_str Zaguán. Repositorio Digital de la Universidad de Zaragoza
collection Zaguán. Repositorio Digital de la Universidad de Zaragoza
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869418076200501248
score 15.300724

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