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Updated: Jun 4, 2026
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Structural Biology and Analytical Chemistry Approaches for Characterizing C-Glycoside Metabolic Enzymes in Human Gut Microbiota
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Multivalent C2-alkyl trihydroxypiperidine architectures modulate β-glucocerebrosidase activity.
Francesca Buco1, Francesca Clemente1, Francesca Cardona1
1Department of Chemistry "Ugo Schiff" (DICUS), University of Florence, Via della Lastruccia 3-13, Sesto Fiorentino, FI, 50019, Italy.
European Journal of Medicinal Chemistry
|June 2, 2026
Summary
Multivalent iminosugars show promise for Gaucher disease. Gold nanoparticle systems effectively rescue mutant GCase in patient cells without toxicity, highlighting scaffold design importance.
Area of Science:
- Biochemistry
- Pharmacology
- Nanotechnology
Background:
- Lysosomal enzyme β-glucocerebrosidase (GCase) deficiency causes Gaucher disease and is linked to Parkinson disease.
- Iminosugars are a class of compounds investigated for modulating GCase activity.
Purpose of the Study:
- To develop and evaluate multivalent iminosugar systems as modulators of GCase.
- To investigate the impact of scaffold organization on enzyme inhibition and functional rescue.
Main Methods:
- Synthesis of C2-alkylated iminosugars multimerized onto tri-/tetrapodal scaffolds and gold nanoparticles.
- Assessment of inhibitory potency and cellular assays using Gaucher patient-derived fibroblasts.
- Evaluation of GCase rescue and cytotoxicity of developed systems.
Main Results:
- Multivalent iminosugar architectures demonstrated enhanced inhibitory potency compared to monovalent compounds.
- Gold nanoparticle-based systems showed a productive chaperone window, rescuing mutant N370S GCase by up to 1.7-fold.
- No detectable cytotoxicity was observed with the gold nanoparticle systems at effective concentrations.
Conclusions:
- Scaffold organization critically influences the balance between enzyme inhibition and functional rescue.
- Multivalent iminosugar systems, particularly those on gold nanoparticles, offer a promising strategy for Gaucher disease treatment.
- These findings emphasize the potential of tailored nanocarrier systems for pharmacological chaperone therapy.
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