Department of Pharmacology , Medical University of Gdańsk , Dębowa 23 , 80-204 Gdańsk , Poland.
Faculty of Chemistry , University of Gdańsk , Wita Stwosza 63 , 80-308 Gdańsk , Poland.
Bioconjug Chem. 2019 Mar 20;30(3):760-774. doi: 10.1021/acs.bioconjchem.8b00894. Epub 2019 Jan 31.
Parkinson's disease (PD) is a common progressive neurodegenerative disorder for which the current treatment is not fully satisfactory. One of the major drawbacks of current PD therapy is poor penetration of drugs across the blood-brain barrier (BBB). In recent years, cell-penetrating peptides (CPPs) such as Tat, SynB, or TP10 have gained great interest due to their ability to penetrate cell membranes and to deliver different cargos to their targets including the central nervous system (CNS). However, there is no data with respect to the use of CPPs as drug carriers to the brain for the treatment of PD. In the presented research, the covalent TP10-dopamine conjugate was synthesized and its pharmacological properties were characterized in terms of its ability to penetrate the BBB and anti-parkinsonian activity. The results showed that dopamine (DA) in the form of a conjugate with TP10 evidently gained access to the brain tissue, exhibited low susceptibility to O-methylation reaction by catechol- O-methyltransferase (lower than that of DA), possessed a relatively high affinity to both dopamine D and D receptors (in the case of D, a much higher than that of DA), and showed anti-parkinsonian activity (higher than that of l-DOPA) in the MPTP-induced preclinical animal model of PD. The presented results prove that the conjugation of TP10 with DA may be a good starting point for the development of a new strategy for the treatment of PD.
帕金森病（PD）是一种常见的进行性神经退行性疾病，目前的治疗方法并不完全令人满意。目前 PD 治疗的主要缺点之一是药物穿过血脑屏障（BBB）的渗透性差。近年来，由于穿透细胞膜的能力以及将不同的有效载荷递送到其靶标（包括中枢神经系统（CNS））的能力，细胞穿透肽（CPP）如 Tat、SynB 或 TP10 引起了极大的兴趣。然而，关于 CPP 作为药物载体用于治疗 PD 的脑内给药，尚无数据。在本研究中，合成了共价连接的 TP10-多巴胺缀合物，并根据其穿透 BBB 的能力和抗帕金森病活性对其药理性质进行了表征。结果表明，以 TP10 与多巴胺形成的缀合物形式明显进入脑组织，对儿茶酚-O-甲基转移酶（COMT）的 O-甲基化反应的敏感性较低（低于多巴胺），对多巴胺 D 和 D 受体均具有较高的亲和力（在 D 的情况下，比多巴胺高得多），并且在 MPTP 诱导的 PD 临床前动物模型中表现出抗帕金森病活性（比 l-DOPA 高）。研究结果证明，TP10 与 DA 的缀合可能是开发治疗 PD 的新策略的良好起点。
