Probing the Inhibitor versus Chaperone Properties of sp2-Iminosugars towards Human -Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease

A series of sp2-iminosugar glycomimetics differing in the reducing or nonreducing character, the configurational pattern (D-gluco or L-ido), the architecture of the glycone skeleton, and the nature of the nonglycone substituent has been synthesized and assayed for their inhibition properties towards...

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Autores: Mena-Barragán, Teresa, García-Moreno, M. Isabel, Sevšek, Alen, Okazaki, Tetsuya, Nanba, Eiji, Higaki, Katsumi, Martin, Nathaniel I., Pieteres, Roland J., García Fernández, José Manuel, Ortiz-Mellet, Carmen
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/164582
Acesso em linha:http://hdl.handle.net/10261/164582
Access Level:acceso abierto
Palavra-chave:sp2-Iminosugars
Deoxynojirimycin
Glycosidase inhibitors
Glucocerebrosidase
Chaperones
Gaucher disease
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spelling Probing the Inhibitor versus Chaperone Properties of sp2-Iminosugars towards Human -Glucocerebrosidase: A Picomolar Chaperone for Gaucher DiseaseMena-Barragán, TeresaGarcía-Moreno, M. IsabelSevšek, AlenOkazaki, TetsuyaNanba, EijiHigaki, KatsumiMartin, Nathaniel I.Pieteres, Roland J.García Fernández, José ManuelOrtiz-Mellet, Carmensp2-IminosugarsDeoxynojirimycinGlycosidase inhibitorsGlucocerebrosidaseChaperonesGaucher diseaseA series of sp2-iminosugar glycomimetics differing in the reducing or nonreducing character, the configurational pattern (D-gluco or L-ido), the architecture of the glycone skeleton, and the nature of the nonglycone substituent has been synthesized and assayed for their inhibition properties towards commercial glycosidases. On the basis of their affinity and selectivity towards GH1 -glucosidases, reducing and nonreducing bicyclic derivatives having a hydroxylation profile of structural complementarity with D-glucose and incorporating an N0-octyl-isourea or -isothiourea segment were selected for further evaluation of their inhibitory/chaperoning potential against human glucocerebrosidase (GCase). The 1-deoxynojirimycin (DNJ)-related nonreducing conjugates behaved as stronger GCase inhibitors than the reducing counterparts and exhibited potent chaperoning capabilities in Gaucher fibroblasts hosting the neuronopathic G188S/G183W mutation, the isothiourea derivative being indeed one of the most efficient chaperone candidates reported up to date (70% activity enhancement at 20 pM). At their optimal concentration, the four selected compounds promoted mutant GCase activity enhancements over 3-fold; yet, the inhibitor/chaperoning balance became unfavorable at much lower concentration for nonreducing as compared to reducing derivatives.Peer reviewedMolecular Diversity Preservation InternationalConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]201820182018info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/164582reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshtpp://dx.doi.org/10.3390/molecules23040927Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1645822026-05-22T06:33:51Z
dc.title.none.fl_str_mv Probing the Inhibitor versus Chaperone Properties of sp2-Iminosugars towards Human -Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease
title Probing the Inhibitor versus Chaperone Properties of sp2-Iminosugars towards Human -Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease
spellingShingle Probing the Inhibitor versus Chaperone Properties of sp2-Iminosugars towards Human -Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease
Mena-Barragán, Teresa
sp2-Iminosugars
Deoxynojirimycin
Glycosidase inhibitors
Glucocerebrosidase
Chaperones
Gaucher disease
title_short Probing the Inhibitor versus Chaperone Properties of sp2-Iminosugars towards Human -Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease
title_full Probing the Inhibitor versus Chaperone Properties of sp2-Iminosugars towards Human -Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease
title_fullStr Probing the Inhibitor versus Chaperone Properties of sp2-Iminosugars towards Human -Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease
title_full_unstemmed Probing the Inhibitor versus Chaperone Properties of sp2-Iminosugars towards Human -Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease
title_sort Probing the Inhibitor versus Chaperone Properties of sp2-Iminosugars towards Human -Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease
dc.creator.none.fl_str_mv Mena-Barragán, Teresa
García-Moreno, M. Isabel
Sevšek, Alen
Okazaki, Tetsuya
Nanba, Eiji
Higaki, Katsumi
Martin, Nathaniel I.
Pieteres, Roland J.
García Fernández, José Manuel
Ortiz-Mellet, Carmen
author Mena-Barragán, Teresa
author_facet Mena-Barragán, Teresa
García-Moreno, M. Isabel
Sevšek, Alen
Okazaki, Tetsuya
Nanba, Eiji
Higaki, Katsumi
Martin, Nathaniel I.
Pieteres, Roland J.
García Fernández, José Manuel
Ortiz-Mellet, Carmen
author_role author
author2 García-Moreno, M. Isabel
Sevšek, Alen
Okazaki, Tetsuya
Nanba, Eiji
Higaki, Katsumi
Martin, Nathaniel I.
Pieteres, Roland J.
García Fernández, José Manuel
Ortiz-Mellet, Carmen
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv sp2-Iminosugars
Deoxynojirimycin
Glycosidase inhibitors
Glucocerebrosidase
Chaperones
Gaucher disease
topic sp2-Iminosugars
Deoxynojirimycin
Glycosidase inhibitors
Glucocerebrosidase
Chaperones
Gaucher disease
description A series of sp2-iminosugar glycomimetics differing in the reducing or nonreducing character, the configurational pattern (D-gluco or L-ido), the architecture of the glycone skeleton, and the nature of the nonglycone substituent has been synthesized and assayed for their inhibition properties towards commercial glycosidases. On the basis of their affinity and selectivity towards GH1 -glucosidases, reducing and nonreducing bicyclic derivatives having a hydroxylation profile of structural complementarity with D-glucose and incorporating an N0-octyl-isourea or -isothiourea segment were selected for further evaluation of their inhibitory/chaperoning potential against human glucocerebrosidase (GCase). The 1-deoxynojirimycin (DNJ)-related nonreducing conjugates behaved as stronger GCase inhibitors than the reducing counterparts and exhibited potent chaperoning capabilities in Gaucher fibroblasts hosting the neuronopathic G188S/G183W mutation, the isothiourea derivative being indeed one of the most efficient chaperone candidates reported up to date (70% activity enhancement at 20 pM). At their optimal concentration, the four selected compounds promoted mutant GCase activity enhancements over 3-fold; yet, the inhibitor/chaperoning balance became unfavorable at much lower concentration for nonreducing as compared to reducing derivatives.
publishDate 2018
dc.date.none.fl_str_mv 2018
2018
2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/164582
url http://hdl.handle.net/10261/164582
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv htpp://dx.doi.org/10.3390/molecules23040927
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Molecular Diversity Preservation International
publisher.none.fl_str_mv Molecular Diversity Preservation International
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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