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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.

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Summary

Multivalent iminosugars show promise for Gaucher disease. Gold nanoparticle systems effectively rescue mutant GCase in patient cells without toxicity, highlighting scaffold design importance.

Keywords:

Gaucher disease Iminosugars Inhibition Multivalent architectures Pharmacological chaperones β-Glucocerebrosidase

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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.