Targeting Glucosylceramide Synthase: Innovative Drug Repurposing Strategies for Lysosomal Diseases

Area of Science:

• Biochemistry
• Pharmacology
• Genetics

Background:

• Sphingolipidoses are rare lysosomal storage diseases with limited treatment options.
• Miglustat is an existing therapy but has significant adverse effects.
• Drug repurposing is a viable strategy for identifying new treatments for rare diseases.

Purpose of the Study:

• To identify novel glucosylceramide synthase (GCS) inhibitors for sphingolipidoses using drug repurposing.
• To evaluate the therapeutic potential of approved drugs as alternatives to Miglustat.
• To assess the efficacy and safety profile of identified candidates.

Main Methods:

• Computational screening of an approved drug library using molecular docking, molecular dynamics, and metadynamics.
• In vitro validation of promising GCS inhibitor candidates.
• Comparative analysis of identified drugs against Miglustat.

Main Results:

• Computational screening identified several potential GCS inhibitors.
• Dapagliflozin emerged as the most promising candidate.
• Experimental validation confirmed Dapagliflozin's efficacy and a potentially favorable side effect profile compared to Miglustat.

Conclusions:

• Drug repurposing, combining computational and experimental methods, is effective for rare disease research.
• Dapagliflozin shows potential as a therapeutic agent for sphingolipidoses.
• Further preclinical and clinical studies are warranted to evaluate Dapagliflozin for sphingolipidoses treatment.