Iminosugar C-Glycosides Work as Pharmacological Chaperones of NAGLU, a Glycosidase Involved in MPS IIIB Rare Disease**

Sha Zhu; Yerri Jagadeesh; Anh Tuan Tran; Shuki Imaeda; Alisdair Boraston; Dominic S. Alonzi; Ana Poveda; Yongmin Zhang; Jérôme Désiré; Julie Charollais-Thoenig; Stéphane Demotz; Atsushi Kato; Terry D. Butters; Jesús Jiménez-Barbero; Matthieu Sollogoub; Yves Blériot

doi:10.1002/chem.202101408

Iminosugar C-Glycosides Work as Pharmacological Chaperones of NAGLU, a Glycosidase Involved in MPS IIIB Rare Disease**

Sha Zhu, Yerri Jagadeesh, Anh Tuan Tran, Shuki Imaeda, Alisdair Boraston, Dominic S. Alonzi, Ana Poveda, Yongmin Zhang, Jérôme Désiré, Julie Charollais-Thoenig, Stéphane Demotz, Atsushi Kato, Terry D. Butters, Jesús Jiménez-Barbero, Matthieu Sollogoub^*, Yves Blériot^*

^*Corresponding author for this work

Hospital Pharmacy

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

Mucopolysaccharidosis type IIIB is a devastating neurological disease caused by a lack of the lysosomal enzyme, α-N-acetylglucosaminidase (NAGLU), leading to a toxic accumulation of heparan sulfate. Herein we explored a pharmacological chaperone approach to enhance the residual activity of NAGLU in patient fibroblasts. Capitalizing on the three-dimensional structures of two modest homoiminosugar-based NAGLU inhibitors in complex with bacterial homolog of NAGLU, CpGH89, we have synthesized a library of 17 iminosugar C-glycosides mimicking N-acetyl-D-glucosamine and bearing various pseudo-anomeric substituents of both α- and β-configuration. Elaboration of the aglycon moiety results in low micromolar selective inhibitors of human recombinant NAGLU, but surprisingly it is the non-functionalized and wrongly configured β-homoiminosugar that was proved to act as the most promising pharmacological chaperone, promoting a 2.4 fold activity enhancement of mutant NAGLU at its optimal concentration.

Original language	English
Pages (from-to)	11291-11297
Number of pages	7
Journal	Chemistry - A European Journal
Volume	27
Issue number	44
DOIs	https://doi.org/10.1002/chem.202101408
State	Published - 2021/08/05

Keywords

X-ray crystallography
glycosidase
iminosugars
pharmacological chaperones

ASJC Scopus subject areas

General Chemistry
Catalysis
Organic Chemistry

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10.1002/chem.202101408

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Zhu, S., Jagadeesh, Y., Tran, A. T., Imaeda, S., Boraston, A., Alonzi, D. S., Poveda, A., Zhang, Y., Désiré, J., Charollais-Thoenig, J., Demotz, S., Kato, A., Butters, T. D., Jiménez-Barbero, J., Sollogoub, M., & Blériot, Y. (2021). Iminosugar C-Glycosides Work as Pharmacological Chaperones of NAGLU, a Glycosidase Involved in MPS IIIB Rare Disease**. Chemistry - A European Journal, 27(44), 11291-11297. https://doi.org/10.1002/chem.202101408

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title = "Iminosugar C-Glycosides Work as Pharmacological Chaperones of NAGLU, a Glycosidase Involved in MPS IIIB Rare Disease**",

abstract = "Mucopolysaccharidosis type IIIB is a devastating neurological disease caused by a lack of the lysosomal enzyme, α-N-acetylglucosaminidase (NAGLU), leading to a toxic accumulation of heparan sulfate. Herein we explored a pharmacological chaperone approach to enhance the residual activity of NAGLU in patient fibroblasts. Capitalizing on the three-dimensional structures of two modest homoiminosugar-based NAGLU inhibitors in complex with bacterial homolog of NAGLU, CpGH89, we have synthesized a library of 17 iminosugar C-glycosides mimicking N-acetyl-D-glucosamine and bearing various pseudo-anomeric substituents of both α- and β-configuration. Elaboration of the aglycon moiety results in low micromolar selective inhibitors of human recombinant NAGLU, but surprisingly it is the non-functionalized and wrongly configured β-homoiminosugar that was proved to act as the most promising pharmacological chaperone, promoting a 2.4 fold activity enhancement of mutant NAGLU at its optimal concentration.",

keywords = "X-ray crystallography, glycosidase, iminosugars, pharmacological chaperones",

author = "Sha Zhu and Yerri Jagadeesh and Tran, {Anh Tuan} and Shuki Imaeda and Alisdair Boraston and Alonzi, {Dominic S.} and Ana Poveda and Yongmin Zhang and J{\'e}r{\^o}me D{\'e}sir{\'e} and Julie Charollais-Thoenig and St{\'e}phane Demotz and Atsushi Kato and Butters, {Terry D.} and Jes{\'u}s Jim{\'e}nez-Barbero and Matthieu Sollogoub and Yves Bl{\'e}riot",

note = "Publisher Copyright: {\textcopyright} 2021 Wiley-VCH GmbH",

year = "2021",

month = aug,

day = "5",

doi = "10.1002/chem.202101408",

language = "英語",

volume = "27",

pages = "11291--11297",

journal = "Chemistry - A European Journal",

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Zhu, S, Jagadeesh, Y, Tran, AT, Imaeda, S, Boraston, A, Alonzi, DS, Poveda, A, Zhang, Y, Désiré, J, Charollais-Thoenig, J, Demotz, S, Kato, A, Butters, TD, Jiménez-Barbero, J, Sollogoub, M & Blériot, Y 2021, 'Iminosugar C-Glycosides Work as Pharmacological Chaperones of NAGLU, a Glycosidase Involved in MPS IIIB Rare Disease**', Chemistry - A European Journal, vol. 27, no. 44, pp. 11291-11297. https://doi.org/10.1002/chem.202101408

TY - JOUR

T1 - Iminosugar C-Glycosides Work as Pharmacological Chaperones of NAGLU, a Glycosidase Involved in MPS IIIB Rare Disease**

AU - Zhu, Sha

AU - Jagadeesh, Yerri

AU - Tran, Anh Tuan

AU - Imaeda, Shuki

AU - Boraston, Alisdair

AU - Alonzi, Dominic S.

AU - Poveda, Ana

AU - Zhang, Yongmin

AU - Désiré, Jérôme

AU - Charollais-Thoenig, Julie

AU - Demotz, Stéphane

AU - Kato, Atsushi

AU - Butters, Terry D.

AU - Jiménez-Barbero, Jesús

AU - Sollogoub, Matthieu

AU - Blériot, Yves

PY - 2021/8/5

Y1 - 2021/8/5

N2 - Mucopolysaccharidosis type IIIB is a devastating neurological disease caused by a lack of the lysosomal enzyme, α-N-acetylglucosaminidase (NAGLU), leading to a toxic accumulation of heparan sulfate. Herein we explored a pharmacological chaperone approach to enhance the residual activity of NAGLU in patient fibroblasts. Capitalizing on the three-dimensional structures of two modest homoiminosugar-based NAGLU inhibitors in complex with bacterial homolog of NAGLU, CpGH89, we have synthesized a library of 17 iminosugar C-glycosides mimicking N-acetyl-D-glucosamine and bearing various pseudo-anomeric substituents of both α- and β-configuration. Elaboration of the aglycon moiety results in low micromolar selective inhibitors of human recombinant NAGLU, but surprisingly it is the non-functionalized and wrongly configured β-homoiminosugar that was proved to act as the most promising pharmacological chaperone, promoting a 2.4 fold activity enhancement of mutant NAGLU at its optimal concentration.

AB - Mucopolysaccharidosis type IIIB is a devastating neurological disease caused by a lack of the lysosomal enzyme, α-N-acetylglucosaminidase (NAGLU), leading to a toxic accumulation of heparan sulfate. Herein we explored a pharmacological chaperone approach to enhance the residual activity of NAGLU in patient fibroblasts. Capitalizing on the three-dimensional structures of two modest homoiminosugar-based NAGLU inhibitors in complex with bacterial homolog of NAGLU, CpGH89, we have synthesized a library of 17 iminosugar C-glycosides mimicking N-acetyl-D-glucosamine and bearing various pseudo-anomeric substituents of both α- and β-configuration. Elaboration of the aglycon moiety results in low micromolar selective inhibitors of human recombinant NAGLU, but surprisingly it is the non-functionalized and wrongly configured β-homoiminosugar that was proved to act as the most promising pharmacological chaperone, promoting a 2.4 fold activity enhancement of mutant NAGLU at its optimal concentration.

KW - X-ray crystallography

KW - glycosidase

KW - iminosugars

KW - pharmacological chaperones

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U2 - 10.1002/chem.202101408

DO - 10.1002/chem.202101408

M3 - 学術論文

C2 - 34106504

AN - SCOPUS:85109341203

SN - 0947-6539

VL - 27

SP - 11291

EP - 11297

JO - Chemistry - A European Journal

JF - Chemistry - A European Journal

IS - 44

ER -

Iminosugar C-Glycosides Work as Pharmacological Chaperones of NAGLU, a Glycosidase Involved in MPS IIIB Rare Disease**

Abstract

Keywords

ASJC Scopus subject areas

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