Discovery of a potent HMG-CoA reductase degrader that eliminates statin-induced reductase accumulation and lowers cholesterol

doi:10.1038/s41467-018-07590-3

	Discovery of a potent HMG-CoA reductase degrader that eliminates statin-induced reductase accumulation and lowers cholesterol
	Jiang, Shi-You 1; Li, Hui 2; Tang, Jing-Jie 3; Wang, Jie 2; Luo, Jie 1; Liu, Bing 2; Wang, Jin-Kai 1; Shi, Xiong-Jie 1; Cui, Hai-Wei 2; Tang, Jie 2; Yang, Fan 2; Qi, Wei4 ; Qiu, Wen-Wei 2; Song, Bao-Liang 1
	2018-12-03
发表期刊	NATURE COMMUNICATIONS
ISSN	2041-1723
卷号	9
发表状态	已发表
DOI	10.1038/s41467-018-07590-3
摘要	Statins 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.
收录类别	SCI ; SCIE
语种	英语
资助项目	National Key Technology RD Program[2015BAK45B00]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000451873600014
出版者	NATURE PUBLISHING GROUP
WOS关键词	COENZYME-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
原始文献类型	Article
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/29045
专题	生命科学与技术学院_PI研究组_戚炜组
通讯作者	Qiu, Wen-Wei; Song, Bao-Liang
作者单位	1.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
推荐引用方式 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).