Hybrids of polyphenolic/quinone acids, the potential preventive and therapeutic drugs for PD: Disaggregate α-Syn fibrils, inhibit inclusions, and repair damaged neurons in mice

  • Eur J Med Chem. 2023 Jan 18;249:115122. doi: 10.1016/j.ejmech.2023.115122.
Ming-Huan Lü  1 ,  Zhen-Ping Wang  2 ,  Li-Zi Xing  2 ,  Wei Zhang  2 ,  Feng Han  2 ,  Guo-Long Huang  2 ,  Wei Liu  2 ,  Yun-Xiao Zhang  3 ,  Ji Xu  4 ,  Jinquan Cui  5
Affiliations
  • 1. Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, Zhengzhou, 450052, China; Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Zhengzhou University, Zhengzhou, 450014, China.
  • 2. Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, Zhengzhou, 450052, China.
  • 3. Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, Zhengzhou, 450052, China. Electronic address: [email protected].
  • 4. School of Basic Medical Science, Neuroscience Research Institute, Academy of Medical Sciences, Zhengzhou University, Kexue Road 100, Zhengzhou, 45000, China. Electronic address: [email protected].
  • 5. Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Zhengzhou University, Zhengzhou, 450014, China. Electronic address: [email protected].
PMID: 36680987 DOI: 10.1016/j.ejmech.2023.115122
Abstract

Neurotoxic α-Syn fibers, the main components of Lewy bodies, play a key role in the development of PD characterized by a progressive loss of dopaminergic neurons. Here, we designed and synthesized the hybrids of polyphenolic/quinone acids. The candidate compounds showed high α-Syn aggregation inhibitory activities in vitro with IC50 down to 1.6 μM. The inhibition went through the aggregation process by stabilizing the conformation of α-Syn proteostasis and preventing β-sheets aggregation, especially in the lag phase. Furthermore, the candidate drugs could disintegrate the preformed varisized aggregates into pony-size aggregates and functional monomers and continually inhibit the re-aggregation. The activities of anti-aggregation and aggregates depolymerization result in the reduction of inclusions in neuron cells. The candidate drugs also show high anti-oxidation and low cytotoxicity. They finally repair the damaged neurons in 6-OHDA-lesioned C57 mice and significantly improve PD-like symptoms of the PD model mice. The hybrids are promising molecules for PD prevention and therapy.© 2022 Elsevier Masson SAS. All rights reserved.

Keywords
Inclusions; Neurons repair; Parkinson's disease; Protein disaggregation; α-Syn aggregation inhibition.
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