3,4,5-Trihydroxypiperidine Based Multivalent Glucocerebrosidase (GCase) Enhancers

Area of Science:

• Medicinal Chemistry
• Glycoscience
• Enzyme Inhibition

Background:

• Gaucher disease is a lysosomal storage disorder caused by deficiency of the glucocerebrosidase (GCase) enzyme.
• Developing potent GCase inhibitors and pharmacological chaperones is crucial for Gaucher disease therapy.
• Multivalency can enhance the binding affinity and efficacy of small molecules.

Purpose of the Study:

• To synthesize novel multivalent trihydroxypiperidine iminosugar derivatives.
• To evaluate their potential as GCase inhibitors and pharmacological chaperones.
• To assess the therapeutic benefit in Gaucher disease models.

Main Methods:

• Copper-catalyzed alkyne-azide cycloaddition (CuAAC) for synthesizing multivalent compounds.
• Enzyme inhibition assays to determine inhibitory potency against GCase.
• Cell-based assays using Gaucher patient fibroblasts to assess GCase activity recovery.
• Thermal denaturation experiments to evaluate enzyme stabilization.

Main Results:

• Five new multivalent iminosugar derivatives were successfully synthesized.
• The multivalent compounds exhibited significantly higher potency as GCase inhibitors compared to a monovalent reference.
• The trivalent derivative (12) demonstrated a 2-fold recovery of GCase activity in patient fibroblasts with L444P/L444P mutations.
• Compound (12) also imparted stability to recombinant GCase in thermal denaturation studies.

Conclusions:

• Multivalent iminosugar derivatives represent a promising strategy for developing potent GCase inhibitors.
• The trivalent derivative (12) shows potential as a pharmacological chaperone for Gaucher disease, particularly for neuropathic forms.
• The ability to stabilize GCase offers additional therapeutic advantages for enzyme replacement therapy.