2. Academic Validation
  3. A new strategy for the treatment of Parkinson's disease: Discovery and bio-evaluation of the first central-targeting tyrosinase inhibitor

A new strategy for the treatment of Parkinson's disease: Discovery and bio-evaluation of the first central-targeting tyrosinase inhibitor

  • Bioorg Chem. 2024 Sep:150:107612. doi: 10.1016/j.bioorg.2024.107612.
Shulei Qi 1,  Lina Guo 1,  Jinxin Liang 1,  Kaixuan Wang 1,  Qinghong Liao 2,  Siyu He 3,  Weiping Lyu 4,  Zimeng Cheng 1,  Jiayi Wang 1,  Xiaojia Luo 1,  Xiaomei Yan 1,  Ziyao Lu 1,  Xiaohan Wang 1,  Ziming Wang 5,  Xuehong Chen 6,  Qi Li 7
Affiliations

Affiliations

  • 1 Department of Medical Pharmacy, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong, People's Republic of China.
  • 2 Department of Medical Pharmacy, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong, People's Republic of China; Shandong Kangqiao Biotechnology Co., Ltd, Qingdao 266033, Shandong, People's Republic of China.
  • 3 Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550004, China.
  • 4 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, People's Republic of China.
  • 5 School of Pharmacy, Binzhou Medical University, Yantai 256699, Shandong, People's Republic of China.
  • 6 Department of Medical Pharmacy, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong, People's Republic of China. Electronic address: chenxuehong@qdu.edu.cn.
  • 7 Department of Medical Pharmacy, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong, People's Republic of China. Electronic address: 511867569@qq.com.
PMID: 38986418 DOI: 10.1016/j.bioorg.2024.107612
Abstract

The high level of Tyrosinase leads to the generation of neuromelanin, further causing the abnormality of redox-related protein level and mediating the occurrence and development of Parkinson's disease (PD). However, the existing Tyrosinase inhibitors are mostly natural product extracts or polyphenolic derivatives, which hindered them from penetrating the blood-brain barrier (BBB). Herein, we obtained a novel Tyrosinase Inhibitor, 2-06 (tyrosinase: monophenolase IC50 = 70.44 ± 22.69 μM, diphenolase IC50 = 1.89 ± 0.64 μM), through the structure-based screening method. The compound 2-06 presented good in vitro and in vivo safety, and can inhibit the Tyrosinase and melanogenesis in B16F10. Moreover, this compound showed neuroprotective effects and Parkinsonism behavior improving function. 2-06 was proved to penetrate the BBB and enter the central nervous system (CNS). The exploration of the binding mode between 2-06 and Tyrosinase provided the foundation for the subsequent structural optimization. This is the first research to develop a central-targeting Tyrosinase Inhibitor, which is crucial for in-depth study on the new strategy for utilizing Tyrosinase inhibitors to treat PD.

Keywords

Central-targeting; Neuromelanin; Parkinson’s disease; Tyrosinase inhibitors.

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