Developing Allosteric Chaperones for GBA1-Associated Disorders-An Integrated Computational and Experimental Approach

Abstract

Gaucher disease; Parkinson’s disease; Glucocerebrosidase

Enfermedad de Gaucher; Enfermedad de Parkinson; Glucocerebrosidasa

Malaltia de Gaucher; Malaltia de Parkinson; Glucocerebrosidasa

Mutations in the GBA1 gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), are associated with Gaucher disease and increased risk of Parkinson’s disease. This study describes the discovery and characterization of novel allosteric pharmacological chaperones for GCase through an innovative computational approach combined with experimental validation. Utilizing virtual screening and structure-activity relationship optimization, researchers identified several compounds that significantly enhance GCase activity and stability across various cellular models, including patient-derived fibroblasts and neuronal cells harboring GBA1 mutations. Among these, compound 3 emerged as a lead candidate, demonstrating the ability to enhance GCase protein levels and enzymatic activity while effectively reducing the accumulation of toxic substrates in neuronal models. Importantly, pharmacokinetic studies revealed that compound 3 has favorable brain penetration, indicating its potential as a disease-modifying therapy for GBA1-related disorders affecting the central nervous system. This research not only offers a framework for developing allosteric GCase modulators but also unveils promising new therapeutic strategies for managing Gaucher disease and Parkinson’s disease. The ability of compound 3 to cross the blood-brain barrier emphasizes its potential significance in addressing neurological symptoms associated with these conditions.

This study received funding from the Michael J. Fox Foundation, the Silverstein Foundation (MJFF 16182), and the Eurostars-2 joint program, which is co-funded by the European Union’s Horizon 2020 research initiative and Innosuisse—Swiss Innovation Agency (E! 113321–CHAPERONE; Ref.: 113321/21/Q). Additional support came from Eureka|Eurostars (https://eurekanetwork.org/programmes/eurostars/, accessed on 6 December 2022), Instituto de Salud Carlos III, EU/Spain (PI20/00728) to M.M-V. MM was supported by an FPU doctoral fellowship (FPU18/05595) from MINECO (Spain). The funders did not influence the study design, data collection and analysis, the decision to publish, or the preparation of the manuscript.