Therapeutic potential of Coumarin-polyphenolic acid hybrids in PD: Inhibition of α-Syn aggregation and disaggregation of preformed fibrils, leading to reduced neuronal inclusion formation.

Autor: Wang ZP; Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, 450052 Zhengzhou, China., Zhang W; Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, 450052 Zhengzhou, China., Xing LZ; Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, 450052 Zhengzhou, China., Zhao YD; Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, 450052 Zhengzhou, China., Xu J; Deparment of Pharmacology, School of Basic Medical Science, Zhengzhou University, Kexue Road 100, 450001 Zhengzhou, China; Neuroscience Research Institute, Academy of Medical Sciences, Zhengzhou University, Kexue Road 100, 450001 Zhengzhou, China. Electronic address: xuji@zzu.edu.cn., Zhang YX; Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, 450052 Zhengzhou, China. Electronic address: zhangyx@zzu.edu.cn.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2024 Feb 01; Vol. 99, pp. 129618. Date of Electronic Publication: 2024 Jan 12.
DOI: 10.1016/j.bmcl.2024.129618
Abstrakt: This study focuses on the discovery of new potential drugs for treating PD by targeting the aggregation of α-Syn. A series of hybrids combining Coumarin and phenolic acid were designed and synthesized. Four particularly promising compounds were identified, showing strong inhibitory effects with IC 50 values ranging from low micromolar to submicromolar concentrations, as low as 0.63 μM. These compounds exhibited a higher binding affinity to α-Syn residues and effectively hindered the entire aggregation process, maintaining the proteostasis conformation of α-Syn and preventing the formation of β-sheet aggregates. This approach holds significant promise for PD prevention. Additionally, these candidate compounds demonstrated the ability to break down preformed α-Syn oligomers and fibrils, resulting in the formation of smaller aggregates and monomers. Moreover, the candidate compounds showed impressive effectiveness in inhibiting α-Syn aggregation within nerve cells, thereby reducing the likelihood of α-Syn inclusion formation resembling Lewy bodies, which highlights their potential for treating PD.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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