Alpha-synuclein is a primary component of Lewy bodies, the pathological hallmark of Parkinson's disease (PD), and both duplication and triplication of the SNCA (alpha-synuclein) locus lead to increased alpha-synuclein levels and familial PD, demonstrating a critical role for alpha-synuclein in PD pathogenesis. We have previously shown that substrate accumulation of GlcCer caused by loss of beta-glucocerebrosidase (GCase) function stabilizes toxic alpha-synuclein oligomers. In addition, PD patients with GCase mutations show earlier disease onset and more frequently undergo cognitive decline. Moreover, sporadic PD patients demonstrate reduced wild-type GCase activity accompanied by GCase substrate accumulation, suggesting that alpha-synuclein accumulation in sporadic PD may also influence GCase lysosomal activity. Thus, developing non-inhibitory GCase modulators to upregulate GCase activity is a highly attractive therapeutic angle for decreasing alpha-synuclein levels, aggregation and formation of toxic fibrils, and for potentially preventing and/or delaying the onset and progression of Parkinson's disease. To identify novel GCase modulators, we plan to screen a drug-like compound library using a novel binding affinity-based fluorescence polarization assay we have recently developed. We also plan to conduct an in silico screen of commercial drug like databases (Zinc) using our recently identified crystal structure of GCase, and will verify our hit compounds using enzyme activity assays and cell-based assays. Combining the results from this screen with our previous SAR studies and structural based drug design, we will design and synthesize novel GCase modulators with more potent binding affinity and better drug-like characteristics. Finally, we plan to further evaluate these GCase modulator candidates for PK/PD, bioavailability, and toxicity in future animal studies. Ultimately, we plan to identify novel chemotype small molecules which will be critical for accelerating the drug discovery process of GCase modulators to target PD pathogenesis.
|Effective start/end date||8/1/17 → 7/31/19|
- Michael J. Fox Foundation for Parkinson's Research (13881)
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.