PROTAC-based degradation of catechol-O-methyltransferase for potential treatment of Parkinson’s disease

Treatment of Parkinson’s disease (PD) has been a significant challenge in biomedical research. Dopamine (DA) replacement is the mainstay of therapeutic approaches. Catechol-O-methyltransferase (COMT), a crucial enzyme that regulates DA level in the body, has emerged as a therapeutic target in clinical PD management. Traditional COMT inhibitors have short half-lives, necessitating high doses and frequent administration, which led to off-target effects. Herein, we have developed the proteolysis-targeting chimeras (PROTACs) capable of degrading endogenous COMT from various PD-related cells and organisms. We first demonstrated the feasibility of COMT degradation using a TRIM-Away strategy. A series of small-molecule-based PROTACs was subsequently designed and synthesized through screening. We discovered that PROTAC efficiently degraded soluble-COMT (S-COMT) from cells, as well as its homologue COMTD1 from C. elegans. Our results indicate that COMT degradation led to elevated DA levels and a reduction in oxidative stress in PD models. Furthermore, PROTAC demonstrated superior efficacy to tolcapone in prolonged PD cell therapy. We also showed that PROTAC could penetrate the blood-brain barrier (BBB) both in vitro and in vivo by using a microfluidic-based device and live mice. The degrader successfully reduced COMT levels in PD model mice, elevating DA concentrations and ameliorating motor dysfunction. Our results thus showed that COMT-targeting PROTACs might hold significant promise in mitigating some of the current problems associated with PD therapy.