Scientists learn how to target ‘undruggable’ Parkinson’s enzymes

Scientists have found a way to target GTPases, molecular switches involved in Parkinson’s disease and other conditions, which were previously considered undruggable. This discovery, led by UCSF researchers, could lead to therapies for diseases linked to GTPase dysfunction. Kevan M. Shokat, senior author, noted that although GTPases have been known for years, there was no reliable method to drug them until now. Their study, published in Cell, opens the door for drug discovery aimed at these enzymes. A key aspect of Parkinson's is the buildup of toxic alpha-synuclein protein in nerve cells. GTPase enzymes like Rit2, which are involved in removing this toxic protein, have been hard to target therapeutically because their flat structure lacks clear binding sites for drugs. However, Shokat’s team used computer modeling and lab testing to identify a cryptic pocket in GTPases, like the SII pocket found in K-Ras (involved in cancer). Their work shows that new drug molecules can be designed to selectively bind to other GTPases, like Rab and Rho, which play roles in Parkinson’s. Though further research and optimization are needed, this breakthrough could lead to more targeted therapies.