Discovery of a potent HMG-CoA reductase degrader that eliminates statin-induced reductase accumulation and lowers cholesterol
Jiang, Shi-You1; Li, Hui2; Tang, Jing-Jie3; Wang, Jie2; Luo, Jie1; Liu, Bing2; Wang, Jin-Kai1; Shi, Xiong-Jie1; Cui, Hai-Wei2; Tang, Jie2; Yang, Fan2; Qi, Wei4; Qiu, Wen-Wei2; Song, Bao-Liang1
2018-12-03
Source PublicationNATURE COMMUNICATIONS
ISSN2041-1723
Volume9
DOI10.1038/s41467-018-07590-3
AbstractStatins are inhibitors of HMG-CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis, and have been clinically used to treat cardiovascular disease. However, a paradoxical increase of reductase protein following statin treatment may attenuate the effect and increase the side effects. Here we present a previously unexplored strategy to alleviate statin-induced reductase accumulation by inducing its degradation. Inspired by the observations that cholesterol intermediates trigger reductase degradation, we identify a potent degrader, namely Cmpd 81, through structure-activity relationship analysis of sterol analogs. Cmpd 81 stimulates ubiquitination and degradation of reductase in an Insig-dependent manner, thus dramatically reducing protein accumulation induced by various statins. Cmpd 81 can act alone or synergistically with statin to lower cholesterol and reduce atherosclerotic plaques in mice. Collectively, our work suggests that inducing reductase degradation by Cmpd 81 or similar chemicals alone or in combination with statin therapy can be a promising strategy for treating cardiovascular disease.
Indexed BySCI
Language英语
Funding ProjectNational Key Technology RD Program[2015BAK45B00]
WOS Research AreaScience & Technology - Other Topics
WOS SubjectMultidisciplinary Sciences
WOS IDWOS:000451873600014
PublisherNATURE PUBLISHING GROUP
WOS KeywordCOENZYME-A REDUCTASE ; LOW-DENSITY-LIPOPROTEIN ; STEROL-INDUCED DEGRADATION ; FEEDBACK-REGULATION ; 3-HYDROXY-3-METHYLGLUTARYL-COA REDUCTASE ; ACCELERATED DEGRADATION ; COMPETITIVE INHIBITOR ; ENDOPLASMIC-RETICULUM ; HUMAN FIBROBLASTS ; UBIQUITIN LIGASE
Original Document TypeArticle
Citation statistics
Cited Times:9[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://kms.shanghaitech.edu.cn/handle/2MSLDSTB/29045
Collection生命科学与技术学院_PI研究组_戚炜组
Corresponding AuthorQiu, Wen-Wei; Song, Bao-Liang
Affiliation1.Wuhan Univ, Inst Adv Studies, Coll Life Sci, Hubei Key Lab Cell Homeostasis, Wuhan 430072, Hubei, Peoples R China
2.East China Normal Univ, Sch Chem & Mol Engn, Shanghai Engn Res Ctr Mol Therapeut & New Drug De, Shanghai 200241, Peoples R China
3.Univ Chinese Acad Sci, Chinese Acad Sci, Inst Biochem & Cell Biol, State Key Lab Mol Biol, Shanghai 200031, Peoples R China
4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
Recommended Citation
GB/T 7714
Jiang, Shi-You,Li, Hui,Tang, Jing-Jie,et al. Discovery of a potent HMG-CoA reductase degrader that eliminates statin-induced reductase accumulation and lowers cholesterol[J]. NATURE COMMUNICATIONS,2018,9.
APA Jiang, Shi-You.,Li, Hui.,Tang, Jing-Jie.,Wang, Jie.,Luo, Jie.,...&Song, Bao-Liang.(2018).Discovery of a potent HMG-CoA reductase degrader that eliminates statin-induced reductase accumulation and lowers cholesterol.NATURE COMMUNICATIONS,9.
MLA Jiang, Shi-You,et al."Discovery of a potent HMG-CoA reductase degrader that eliminates statin-induced reductase accumulation and lowers cholesterol".NATURE COMMUNICATIONS 9(2018).
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