Developing a cell-based high throughput screening for USP15 deubiquitinase inhibitor discovery

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Developing a cell-based high throughput screening for USP15 deubiquitinase inhibitor discovery The goal of this project is to develop a ubiquitin probe-based AlphaLISA deubiquitinase HTS assay that enables cell-based and high throughput screening for human deubiquitinase USP15. It is now clear that the human ubiquitin system is fundamentally important to the normal cellular and organismal functions. Deubiquitinases or DUBs as an important class of enzyme have been associated with neurological disorders, particularly Parkinson’s disease (PD). Many disease-relevant and potentially druggable deubiquitinases are currently inaccessible to HTS-based inhibitor discovery due to the difficulty in their purification as homogeneous and active recombinant proteins in quantity large enough for HTS campaign. In this proposal, we aim at developing a cell-based AlphaLISA deubiquitinase assay for high throughput screening against USP15 and other DUBs, and setting the ground work for identifying and developing USP15 inhibitors with a mitophagy-promoting effect and the potential being developed into PD therapeutics.