Acetal functionalized iminosugars for targeting β-glucocerebrosidase modulation.

Area of Science:

• Biochemistry
• Drug Delivery
• Personalized Medicine

Background:

• Lysosomal enzyme β-glucocerebrosidase (GCase) dysfunction is implicated in Gaucher and Parkinson's diseases.
• Current pharmacological chaperones (PCs) for GCase show limited efficacy due to poor dissociation from the enzyme in lysosomes.
• Oxidative stress is a significant factor in Gaucher and Parkinson's disease pathogenesis.

Purpose of the Study:

• To develop novel pH-sensitive drug delivery systems for enhanced GCase stabilization and targeted therapy.
• To design compounds that dissociate in acidic lysosomal environments, improving therapeutic outcomes.
• To incorporate antioxidant moieties to combat oxidative stress associated with GCase-related diseases.

Main Methods:

• Synthesis of pH-sensitive acetal functionalized iminosugars incorporating antioxidant moieties (coniferyl aldehyde and vanillin).
• Evaluation of pH sensitivity and GCase stabilization in ex vivo fibroblast assays.
• Validation of compound efficacy in both cell lysates and intact cells.

Main Results:

• Compounds 1-4 demonstrated varying degrees of pH sensitivity and GCase stabilization.
• Acetal 4 exhibited promising pH-dependent dissociation and GCase stabilization properties.
• The synthesized compounds were validated in both cellular lysates and intact cell models.

Conclusions:

• pH-sensitive acetal functionalized iminosugars represent a promising strategy for targeted drug delivery in lysosomal storage disorders.
• The developed system effectively exploits acidic environments for controlled drug release and dissociation.
• Acetal 4 shows potential for therapeutic intervention in Gaucher and Parkinson's diseases by stabilizing GCase and reducing oxidative stress.