Identification of Modulators of the N370S Mutant Form of Glucocerebrosidase as a Potential Therapy for Gaucher Disease

National Center For Advancing Translational Sciences

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Abstract

During this period, the project team has continued to develop and characterize small molecule modulators of glucocerebrosidase for Gaucher's disease and Parkinson's disease. We have continued to implement a comprehensive cell-based discovery approach to identify molecules that increase levels of the L444P variant of GBA1, pursuing non-inhibitory pharmacological chaperones of the enzyme. High-throughput screening amenable cell-based assays were refined and implemented during the last year. We have also continued to develop and test fluorogenic probes that can report on lysosomal activity of GBA1. Additionally, molecular modeling studies and virtual screening have been performed to predict molecules that would function as non-inhibitory chaperones; activity of these compounds has been characterized in the high-throughput assay. Finally, we have continued to advance our capabilities for large scale production of iPSC derived cells that show disease relevant phenotypes.