Promising Outcomes of Original Grant:
The protein Parkin requires activation by another enzyme called PINK1. With previous MJFF funding, we identified a new class of chemical fragments that could be become Parkin activators. These fragments have a structure very similar to the amino acid that, once mutated, activates Parkin, but they don't bind specifically to Parkin and we don't yet know if they can activate the protein.
Objectives for Supplemental Investigation:
The goal of this investigation is to design compounds with improved binding for Parkin, starting from the chemical fragments we discovered in the previous grant. In collaboration with a medicinal chemist, we plan to make and order derivatives of the chemical fragment that could bind to Parkin and provide new starting point for compound design. We will test these compounds for binding to Parkin and their ability to increase its activity.
Importance of This Research for the Development of a New PD Therapy:
Loss of Parkin activity has been associated with both familial Parkinson's through inherited genetic mutations, as well as the more common sporadic form of the disease. Numerous studies have shown that Parkin activity protects brain cells in models of Parkinson's. Small molecule activators of Parkin developed in this proposal will be the starting points for the design of potent Parkin activators that could become Parkinson's drugs.