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sp 2 -Iminosugar azobenzene O-glycosides: Light-sensitive glycosidase inhibitors with unprecedented tunability and switching factors.
- Source :
-
Bioorganic chemistry [Bioorg Chem] 2024 Sep; Vol. 150, pp. 107555. Date of Electronic Publication: 2024 Jun 12. - Publication Year :
- 2024
-
Abstract
- The conventional approach to developing light-sensitive glycosidase activity regulators, involving the combination of a glycomimetic moiety and a photoactive azobenzene module, results in conjugates with differences in glycosidase inhibitory activity between the interchangeable E and Z-isomers at the azo group that are generally below one-order of magnitude. In this study, we have exploited the chemical mimic character of sp <superscript>2</superscript> -iminosugars to access photoswitchable p- and o-azobenzene α-O-glycosides based on the gluco-configured representative ONJ. Notably, we achieved remarkably high switching factors for glycosidase inhibition, favoring either the E- or Z-isomer depending on the aglycone structure. Our data also indicate a correlation between the isomeric state of the azobenzene module and the selectivity towards α- and β-glucosidase isoenzymes. The most effective derivative reached over a 10 <superscript>3</superscript> -fold higher inhibitory potency towards human β-glucocerebrosidase in the Z as compared with the E isomeric form. This sharp contrast is compatible with ex-vivo activation and programmed self-deactivation at physiological temperatures, positioning it as a prime candidate for pharmacological chaperone therapy in Gaucher disease. Additionally, our results illustrate that chemical tailoring enables the engineering of photocommutators with the ability to toggle inhibition between α- and β-glucosidase enzymes in a reversible manner, thus expanding the versatility and potential therapeutic applications of this approach.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024. Published by Elsevier Inc.)
- Subjects :
- Humans
Dose-Response Relationship, Drug
Light
Molecular Structure
Structure-Activity Relationship
Glucosylceramidase chemistry
Glucosylceramidase metabolism
Glucosylceramidase pharmacology
Azo Compounds chemistry
Azo Compounds pharmacology
Azo Compounds chemical synthesis
Enzyme Inhibitors chemistry
Enzyme Inhibitors pharmacology
Enzyme Inhibitors chemical synthesis
Glycoside Hydrolases antagonists & inhibitors
Glycoside Hydrolases metabolism
Glycosides chemistry
Glycosides pharmacology
Glycosides chemical synthesis
Imino Sugars chemistry
Imino Sugars pharmacology
Imino Sugars chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2120
- Volume :
- 150
- Database :
- MEDLINE
- Journal :
- Bioorganic chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38885548
- Full Text :
- https://doi.org/10.1016/j.bioorg.2024.107555