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<p>Treatment of Parkinson’s disease (PD) has been a significant challenge in biomedical research. Dopamine (DA) replacement is the mainstay of therapeutic approaches. Catechol-<i>O</i>-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 (<i>S</i>-COMT) from cells, as well as its homologue COMTD1 from <i>C. elegans</i>. 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 <i>in vitro</i> and <i>in vivo</i> 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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年1月4日

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  • Haixiao Fang,
  • Panpan Li,
  • Qi Gao,
  • Shubo Du,
  • Jing Gu,
  • Xia Liu,
  • Bo Peng,
  • Hua Bai,
  • Cheng-Wu Zhang,
  • Lin Li,
  • Shao Q. Yao

摘要

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.