Inhibitors of Poly (ADP-Ribose) Glycohydrolase (PARG) as Novel Agents for the Treatment of PD
Target Validation, 2005
It has become increasingly clear that the death of mid-brain neurons in Parkinson's disease patients is associated with the activation of certain enzymes that add sugar units onto various proteins. In addition, provocative data suggests that compounds that strongly and selectively inhibit these enzymes would be powerful neuroprotective agents. Unfortunately, for a variety of reasons it has been difficult to identify such compounds.
We propose a comprehensive plan to identify drug-like small molecules that specifically inhibit these enzymes. The effect of these compounds will then be validated in cell culture and animal models of Parkinson's disease; thus, we intend to use small molecules to identify a novel target for the treatment of Parkinson's disease.
Dr. Hergenrother made substantial progress in identifying compounds that targeted the enzyme of interest, PARG. He identified the first cell-permeable PARG inhibitor and discovered a new class of PARG inhibitors. While the results of testing these compounds in PD models were unclear, additional work will help to determine whether PARG inhibitors are a viable therapeutic approach for PD.
Professor, Department of Chemistry at University of Illinois, Urbana-Champaign