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A series of glycomimetics of UDP-GlcNAc, in which the β-phosphate has been replaced by either an alkyl chain or a triazolyl ring and the sugar moiety has been replaced by a pyrrolidine ring, has been synthesized by the application of different click-chemistry procedures.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

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Autores: Ghirardello, Mattia, Perrone, Daniela, Chinaglia, Nicola, Sádaba, David, Delso, J. Ignacio, Tejero, Tomás, Marchesi, Elena, Fogagnolo, Marco, Rafie, Karim, Aalten, Daan M. F. Van, Merino, Pedro
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2018
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/187097
Acceso en línea:http://hdl.handle.net/10261/187097
Access Level:acceso abierto
Palabra clave:Bioconjugates
Carbohydrates
Glycosylation
Glycosyltransferases
Nucleotide diphosphate analogues
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spelling UDP‐GlcNAc analogues as inhibitors of O‐GlcNAc transferase (OGT): Spectroscopic, computational, and biological studiesGhirardello, MattiaPerrone, DanielaChinaglia, NicolaSádaba, DavidDelso, J. IgnacioTejero, TomásMarchesi, ElenaFogagnolo, MarcoRafie, KarimAalten, Daan M. F. VanMerino, PedroBioconjugatesCarbohydratesGlycosylationGlycosyltransferasesNucleotide diphosphate analoguesA series of glycomimetics of UDP-GlcNAc, in which the β-phosphate has been replaced by either an alkyl chain or a triazolyl ring and the sugar moiety has been replaced by a pyrrolidine ring, has been synthesized by the application of different click-chemistry procedures.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.We thank for their support of our programs: MINECO (Madrid, Spain), the FEDER Program (Project CTQ2016-76155-R), and the Government of Aragon (Group E-10) to P.M; a Wellcome Investigator Award (110061) to DMFvA, and the University of Ferrara (FAR2016) to D.P. and M.F. M.G. thanks the MECD for an FPU pre-doctoral grant. D.S. thanks the CSIC for a JAE-Pre pre-doctoral grant. KR is funded by a BBSRC Studentship (1416998)Peer reviewedWiley-VCHBiotechnology and Biological Sciences Research Council (UK)Ministerio de Economía y Competitividad (España)Gobierno de AragónConsejo Superior de Investigaciones Científicas (España)Ministerio de Educación, Cultura y Deporte (España)European CommissionUniversità degli Studi di FerraraWellcomeConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]201920192018info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Postprintinfo:eu-repo/semantics/acceptedVersionhttp://hdl.handle.net/10261/187097reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/CTQ2016-76155-Rhttps://doi.org/10.1002/chem.201801083Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1870972026-05-22T06:33:51Z
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, Mattia
Bioconjugates
Carbohydrates
Glycosylation
Glycosyltransferases
Nucleotide diphosphate analogues
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, Mattia
Perrone, Daniela
Chinaglia, Nicola
Sádaba, David
Delso, J. Ignacio
Tejero, Tomás
Marchesi, Elena
Fogagnolo, Marco
Rafie, Karim
Aalten, Daan M. F. Van
Merino, Pedro
author Ghirardello, Mattia
author_facet Ghirardello, Mattia
Perrone, Daniela
Chinaglia, Nicola
Sádaba, David
Delso, J. Ignacio
Tejero, Tomás
Marchesi, Elena
Fogagnolo, Marco
Rafie, Karim
Aalten, Daan M. F. Van
Merino, Pedro
author_role author
author2 Perrone, Daniela
Chinaglia, Nicola
Sádaba, David
Delso, J. Ignacio
Tejero, Tomás
Marchesi, Elena
Fogagnolo, Marco
Rafie, Karim
Aalten, Daan M. F. Van
Merino, Pedro
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Biotechnology and Biological Sciences Research Council (UK)
Ministerio de Economía y Competitividad (España)
Gobierno de Aragón
Consejo Superior de Investigaciones Científicas (España)
Ministerio de Educación, Cultura y Deporte (España)
European Commission
Università degli Studi di Ferrara
Wellcome
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Bioconjugates
Carbohydrates
Glycosylation
Glycosyltransferases
Nucleotide diphosphate analogues
topic Bioconjugates
Carbohydrates
Glycosylation
Glycosyltransferases
Nucleotide diphosphate analogues
description 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.
publishDate 2018
dc.date.none.fl_str_mv 2018
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Postprint
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/187097
url http://hdl.handle.net/10261/187097
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/CTQ2016-76155-R
https://doi.org/10.1002/chem.201801083
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Wiley-VCH
publisher.none.fl_str_mv Wiley-VCH
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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