Exploration of novel 20S proteasome activators featuring anthraquinone structures and their application in hypoxic cardiomyocyte protection

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2024-10-31 DOI:10.1016/j.bmc.2024.117983

Qian Yu , Lixin Gao , Linhao Xu , Yubing Han , Yu Cao , Jianjun Xi , Yigang Zhong , Linjie Li , Liteng Shen , Jinxin Che , Xiaowu Dong , Chong Zhang , Linghui Zeng , Huajian Zhu , Jiaan Shao , Yizhou Xu , Jia Li , Yubo Zhou , Jiankang Zhang

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引用次数: 0

Abstract

Under hypoxic conditions, the accumulation of misfolded proteins primarily relies on the autonomous activity of 20S proteasome for degradation. The buildup of toxic proteins in cardiomyocyte contribute to various cardiovascular diseases. Therefore, enhancing the 20S proteasome degradation capacity and restoring protein homeostasis in myocardial cells with small molecule activators represent a promising therapeutic strategy for the treatment of ischemic cardiomyopathy. In this study, the lead compound 8016–8398 was identified through virtual screening, and subsequent structure optimization resulted in a series of highly potent 20S proteasome activators. Intracellular protein degradation assessment revealed that these compounds possessed abilities to alleviate endoplasmic reticulum stress, as demonstrated by the luciferase reporter system. Additionally, selected compound B-03 significantly enhanced the survival rate of hypoxic-damaged cardiomyocytes. Mechanistic investigations verified B-03 rescued hypoxic damaged cardiomyocyte through apoptosis inhibition and proliferation promotion.

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探索具有蒽醌结构的新型 20S 蛋白酶体激活剂及其在缺氧性心肌细胞保护中的应用

在缺氧条件下，错误折叠蛋白的积累主要依靠 20S 蛋白酶体的自主降解活动。有毒蛋白质在心肌细胞中的堆积会导致各种心血管疾病。因此，利用小分子激活剂提高 20S 蛋白酶体的降解能力并恢复心肌细胞中的蛋白质平衡是治疗缺血性心肌病的一种很有前景的治疗策略。在这项研究中，通过虚拟筛选确定了先导化合物 8016-8398，并在随后的结构优化中开发出了一系列高效的 20S 蛋白酶体激活剂。细胞内蛋白质降解评估显示，这些化合物具有缓解内质网应激的能力，这一点已在荧光素酶报告系统中得到证实。此外，所选化合物 B-03 还能显著提高缺氧损伤心肌细胞的存活率。机理研究证实，B-03 可通过抑制细胞凋亡和促进细胞增殖来挽救缺氧损伤的心肌细胞。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.