Grant: Project Grant

Our team has been designing and developing inhibitors against prolyl oligopeptidase, an enzyme which has gained interest as a drug target for its high level of activity in Parkinson's disease patients and its link to alpha-synuclein aggregation. In state-of-the-art biological models of Parkinson's disease, we confirmed that our inhibitors reduced alpha-synuclein aggregation in living neurons. However, while this research has successfully identified inhibitors which are potent, non toxic to neurons, blood brain barrier permeant and metabolically stable inhibitors, additional evaluations, target engagement experiments as well as medicinal chemistry optimization are now required to take us a considerable step towards a drug candidate. In the next three years, 1) the target (prolyl oligopeptidase) will be further validated (e.g., target engagement, KO mouse, in vivo evaluation), 2) our current lead molecules at the different stage of the pipeline (newly discovered inhibitors, potent inhibitors with potency in neurons and promising DMPK profiles, and inhibitors being tested in a mouse PD model) with will be further advanced. The later objectives include the confirmation of the mode of action through crystallography and the evaluation and optimization of in vitro and in vivo drug properties including in vivo efficacy through chemical modifications and experimental evaluation of the improved properties. This proposed research will advance these molecules closer to clinical trials.