Discovery of novel 20S proteasome activators for hypoxic cardiomyocyte protection via endoplasmic reticulum stress alleviation
文献类型：期刊论文
| 作者 | Wu, Dan6; Cao, Yu2; Han, Yubing1,3; Xu, Linhao5; Han, Han6; Shi, Yaoli6; Ma, Jiayi6; Wang, Qingyi6; Gao, Lixin3; Wang, Mingzhi1 |
| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY
 |
| 出版日期 | 2026 |
| 卷号 | 132页码:15 |
| 关键词 | 20S proteasome activator Proteostasis Screening and optimization ER stress Hypoxic cardiomyocyte protection |
| ISSN号 | 0968-0896 |
| DOI | 10.1016/j.bmc.2025.118452 |
| 英文摘要 | Under hypoxic stress, cardiomyocytes predominantly depend on 20S proteasome-mediated degradation to clear accumulated and misfolded proteins. The resultant proteotoxic stress from impaired protein homeostasis contributes significantly to the pathogenesis of cardiovascular disorders. Pharmacological enhancement of 20S proteasome activity thus represents a novel therapeutic paradigm for ischemic cardiomyopathy by restoring proteostasis in myocardial cells. In this study, the hit compound X-1 was identified through screening of proteasome activation profile. Subsequent structure-activity relationship optimization yielded a series of highly potent 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 B3 exhibited superior cytoprotection, increasing viability of hypoxia-injured cardiomyocytes while downregulating ER stress markers CHOP and Grp78 at the protein level. AlphaFold3-predicted binding modes and 100 ns molecular dynamics simulations revealing its stabilization of the alpha region to induce proteasome gate opening, thereby establishing a structure-function rationale for its 20S activation mechanism. |
| WOS关键词 | PROTEOSTASIS |
| 资助项目 | Hangzhou Natural Science Foundation[2024SZRYBH300001] ; Zhejiang Provincial Natural Science Foundation of China[LY24H300003] ; Zhejiang Provincial Natural Science Foundation of China[LTGY24B020001] ; Medical Health Science and Technology Project of Zhejiang Provincial Health Commission[2023KY973] ; Medical Health Science and Technology Project of Zhejiang Provincial Health Commission[2024KY210] ; Medical Health Science and Technology General Project of Hangzhou Health Commission[A20230710] ; Medical Health Science and Technology General Project of Hangzhou Health Commission[A20230089] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001611916000002 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/321726]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Xu, Yizhou; Zhou, Yubo; Zhang, Jiankang |
| 作者单位 | 1.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China 2.Hangzhou Xixi Hosp, Dept Pharmaceut Preparat, Hangzhou 310023, Zhejiang, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 4.Hangzhou SanOmics Informat Technol Co Ltd, Hangzhou 310015, Peoples R China 5.Westlake Univ, Affiliated Hangzhou Peoples Hosp 1, Sch Med, Dept Cardiol, Hangzhou 310006, Zhejiang, Peoples R China 6.Hangzhou City Univ, Sch Med, Hangzhou 310015, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wu, Dan,Cao, Yu,Han, Yubing,et al. Discovery of novel 20S proteasome activators for hypoxic cardiomyocyte protection via endoplasmic reticulum stress alleviation[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2026,132:15. |
| APA | Wu, Dan.,Cao, Yu.,Han, Yubing.,Xu, Linhao.,Han, Han.,...&Zhang, Jiankang.(2026).Discovery of novel 20S proteasome activators for hypoxic cardiomyocyte protection via endoplasmic reticulum stress alleviation.BIOORGANIC & MEDICINAL CHEMISTRY,132,15. |
| MLA | Wu, Dan,et al."Discovery of novel 20S proteasome activators for hypoxic cardiomyocyte protection via endoplasmic reticulum stress alleviation".BIOORGANIC & MEDICINAL CHEMISTRY 132(2026):15. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。