Funded Studies
Objective/Rationale:
There is a great need to discover novel therapeutic targets and strategies that halt or reverse the progression of Parkinson’s disease (PD). In this study we hope to identify compounds that inhibit the aggregation of the protein alpha-synuclein, the hallmark pathology of PD. Such a compound has the potential to impact disease progression, thus could be a candidate compound for disease-modifying therapeutics.
Project Description:
We will screen the NIH Drug Collection for drugs that inhibit alpha-synclein aggregation and toxicity using a sensitive, cell-based assay that can monitor alpha-synuclein aggregation.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Current drugs to treat Parkinson’s disease patients only treat the symptoms of the disease; none can slow down or stop disease progression. If we can successfully identify a drug that blocks alpha-synuclein aggregation, it would have the potential to be developed as a novel disease-modifying therapeutic for PD.
Anticipated Outcome:
If our screening strategy is successful we hope to identify two to three lead compounds that we can then go on to further validate in pre-clinical models and human neurons with the eventual goal of identifying a drug-like compound that can be further developed as a PD therapeutic.
Final Outcome
We have successfully completed the original aims of this study. We have performed an ultra-high-throughput drug screen of more than 370,000 compounds for inhibitors of alpha-synuclein aggregation.
We initially identified 1911 compounds that could reduce alpha-synuclein aggregation. Confirmation studies reduced that number to 110 compounds with diverse chemical structures. Further screening identified 8 compounds that met all the criteria to move forward. Subsequent studies on analogs of these 8 compounds have resulted in improved compounds. Ultimately, we have identified three unique chemical series in this two year effort. These compounds offer several opportunities for further medicinal chemistry efforts. To the best of our knowledge these series represent first in class inhibitors of alpha-synuclein oligomer formation.