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Probing the Inhibitor versus Chaperone Properties of sp(2)-Iminosugars towards Human β-Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease

A series of sp(2)-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 towar...

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Autores principales: Mena-Barragán, Teresa, García-Moreno, M. Isabel, Sevšek, Alen, Okazaki, Tetsuya, Nanba, Eiji, Higaki, Katsumi, Martin, Nathaniel I., Pieters, Roland J., Fernández, José M. García, Mellet, Carmen Ortiz
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017062/
https://www.ncbi.nlm.nih.gov/pubmed/29673163
http://dx.doi.org/10.3390/molecules23040927
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author Mena-Barragán, Teresa
García-Moreno, M. Isabel
Sevšek, Alen
Okazaki, Tetsuya
Nanba, Eiji
Higaki, Katsumi
Martin, Nathaniel I.
Pieters, Roland J.
Fernández, José M. García
Mellet, Carmen Ortiz
author_facet Mena-Barragán, Teresa
García-Moreno, M. Isabel
Sevšek, Alen
Okazaki, Tetsuya
Nanba, Eiji
Higaki, Katsumi
Martin, Nathaniel I.
Pieters, Roland J.
Fernández, José M. García
Mellet, Carmen Ortiz
author_sort Mena-Barragán, Teresa
collection PubMed
description A series of sp(2)-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 β-glucosidases, reducing and nonreducing bicyclic derivatives having a hydroxylation profile of structural complementarity with d-glucose and incorporating an N′-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.
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spelling pubmed-60170622018-11-13 Probing the Inhibitor versus Chaperone Properties of sp(2)-Iminosugars towards Human β-Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease Mena-Barragán, Teresa García-Moreno, M. Isabel Sevšek, Alen Okazaki, Tetsuya Nanba, Eiji Higaki, Katsumi Martin, Nathaniel I. Pieters, Roland J. Fernández, José M. García Mellet, Carmen Ortiz Molecules Article A series of sp(2)-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 β-glucosidases, reducing and nonreducing bicyclic derivatives having a hydroxylation profile of structural complementarity with d-glucose and incorporating an N′-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. MDPI 2018-04-17 /pmc/articles/PMC6017062/ /pubmed/29673163 http://dx.doi.org/10.3390/molecules23040927 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Mena-Barragán, Teresa
García-Moreno, M. Isabel
Sevšek, Alen
Okazaki, Tetsuya
Nanba, Eiji
Higaki, Katsumi
Martin, Nathaniel I.
Pieters, Roland J.
Fernández, José M. García
Mellet, Carmen Ortiz
Probing the Inhibitor versus Chaperone Properties of sp(2)-Iminosugars towards Human β-Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease
title Probing the Inhibitor versus Chaperone Properties of sp(2)-Iminosugars towards Human β-Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease
title_full Probing the Inhibitor versus Chaperone Properties of sp(2)-Iminosugars towards Human β-Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease
title_fullStr Probing the Inhibitor versus Chaperone Properties of sp(2)-Iminosugars towards Human β-Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease
title_full_unstemmed Probing the Inhibitor versus Chaperone Properties of sp(2)-Iminosugars towards Human β-Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease
title_short Probing the Inhibitor versus Chaperone Properties of sp(2)-Iminosugars towards Human β-Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease
title_sort probing the inhibitor versus chaperone properties of sp(2)-iminosugars towards human β-glucocerebrosidase: a picomolar chaperone for gaucher disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017062/
https://www.ncbi.nlm.nih.gov/pubmed/29673163
http://dx.doi.org/10.3390/molecules23040927
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