Lysosomal Targeting of β-Cyclodextrin
© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH..
β-Cyclodextrin (β-CD) and derivatives are approved therapeutics in >30 clinical settings. β-CDs have also shown promise as therapeutics for treatment of some lysosomal storage disorders, such as Niemann-Pick disease type C, and other disease states which involve metabolite accumulation in the lysosome. In these cases, β-CD activity relies on transport to the lysosome, wherein it can bind hydrophobic substrate and effect extraction. The post-translational attachment of N-glycans terminated in mannose-6-phosphate (M6P) residues is the predominant method by which lysosomal enzymes are targeted to the lysosome. In this work we covalently attach a synthetic biantennary bis-M6P-terminated N-glycan to β-CD and study the effect of the added glycans in a mammalian cell line. The formation of a host guest complex with a Cy5 fluorophore allows study of both cellular internalisation and transport to the lysosome by fluorescence microscopy. Results indicate that the rates of both internalisation and lysosomal transport are increased by the attachment of M6P-glycans to β-CD, indicating that M6P-glycan conjugation may improve the therapeutic effectiveness of β-CD for the treatment of disorders involving hydrophobic metabolite accumulation in the lysosome.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:29 |
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| Enthalten in: |
Chemistry (Weinheim an der Bergstrasse, Germany) - 29(2023), 4 vom: 18. Jan., Seite e202203252 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mascherpa, Andrea [VerfasserIn] |
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| Links: |
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| Themen: |
Beta-Cyclodextrins |
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| Anmerkungen: |
Date Completed 23.01.2023 Date Revised 15.04.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/chem.202203252 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH. | ||
| 520 | |a β-Cyclodextrin (β-CD) and derivatives are approved therapeutics in >30 clinical settings. β-CDs have also shown promise as therapeutics for treatment of some lysosomal storage disorders, such as Niemann-Pick disease type C, and other disease states which involve metabolite accumulation in the lysosome. In these cases, β-CD activity relies on transport to the lysosome, wherein it can bind hydrophobic substrate and effect extraction. The post-translational attachment of N-glycans terminated in mannose-6-phosphate (M6P) residues is the predominant method by which lysosomal enzymes are targeted to the lysosome. In this work we covalently attach a synthetic biantennary bis-M6P-terminated N-glycan to β-CD and study the effect of the added glycans in a mammalian cell line. The formation of a host guest complex with a Cy5 fluorophore allows study of both cellular internalisation and transport to the lysosome by fluorescence microscopy. Results indicate that the rates of both internalisation and lysosomal transport are increased by the attachment of M6P-glycans to β-CD, indicating that M6P-glycan conjugation may improve the therapeutic effectiveness of β-CD for the treatment of disorders involving hydrophobic metabolite accumulation in the lysosome | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Ishii, Nozomii |e verfasserin |4 aut | |
| 700 | 1 | |a Tayagui, Ayelen |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Jiang |e verfasserin |4 aut | |
| 700 | 1 | |a Sollogoub, Matthieu |e verfasserin |4 aut | |
| 700 | 1 | |a Fairbanks, Antony J |e verfasserin |4 aut | |
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