Discovery of Natural Potent HMG-CoA Reductase Degraders for Lowering Cholesterol

doi:10.1002/anie.202313859

KIB OpenIR

	Discovery of Natural Potent HMG-CoA Reductase Degraders for Lowering Cholesterol
	Su,Xiao-Zheng; Zhang,Lin-Fei; Hu,Kun; An,Yang; Zhang,Qiao-Peng; Tang,Jian-Wei; Yan,Bing-Chao; Li,Xing-Ren; Cai,Jie; Li,Xiao-Nian; Sun,Han-Dong; Jiang,Shi-You; Puno,Pema-Tenzin
	2023
发表期刊	ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
ISSN	1521-3773
摘要	Exploitation of key protected wild plant resources makes great sense, but their limited populations become the major barrier. A particular strategy for breaking this barrier was inspired by the exploration of a resource-saving fungal endophyte Penicillium sp. DG23, which inhabits the key protected wild plant Schisandra macrocarpa. Chemical studies on the cultures of this strain afforded eight novel indole diterpenoids, schipenindolenes A-H (1-8), belonging to six diverse skeleton types. Importantly, semisyntheses suggested some key nonenzymatic reactions constructing these molecules and provided targeted compounds, in particular schipenindolene A (Spid A, 1) with low natural abundance. Remarkably, Spid A was the most potent HMG-CoA reductase (HMGCR) degrader among the indole diterpenoid family. It degraded statin-induced accumulation of HMGCR protein, decreased cholesterol levels and acted synergistically with statin to further lower cholesterol. Mechanistically, transcriptomic and proteomic profiling suggested that Spid A potentially activated the endoplasmic reticulum-associated degradation (ERAD) pathway to enhance the degradation of HMGCR, while simultaneously inhibiting the statin-activated expression of many key enzymes in the cholesterol and fatty acid synthesis pathways, thereby strengthening the efficacy of statins and potentially reducing the side effects of statins. Collectively, this study suggests the potential of Spid A for treating cardiovascular disease. The plant Schisandra macrocarpa was explored for the extraction of novel compounds from its fungal endophyte Penicillium sp. DG23. Of the indole diterpenoids and derivatives identified, biological evaluation highlighted schipenindolene A as a potent HMGCR degrader that further lowered cholesterol with statin (HMGCR inhibitor) by activating the endoplasmic reticulum-associated degradation pathway and inhibiting the compensatory effects of statin.+image
关键词	Enzymes Meroterpenoids Natural Products Proteomics Semisynthesis STATIN FUNGUS RISK ACID
DOI	10.1002/anie.202313859
收录类别	SCI
WOS记录号	WOS:001127513700001
引用统计
文献类型	期刊论文
条目标识符	http://ir.kib.ac.cn/handle/151853/75331
专题	中国科学院昆明植物研究所
推荐引用方式 GB/T 7714	Su,Xiao-Zheng,Zhang,Lin-Fei,Hu,Kun,et al. Discovery of Natural Potent HMG-CoA Reductase Degraders for Lowering Cholesterol[J]. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,2023.
APA	Su,Xiao-Zheng.,Zhang,Lin-Fei.,Hu,Kun.,An,Yang.,Zhang,Qiao-Peng.,...&Puno,Pema-Tenzin.(2023).Discovery of Natural Potent HMG-CoA Reductase Degraders for Lowering Cholesterol.ANGEWANDTE CHEMIE-INTERNATIONAL EDITION.
MLA	Su,Xiao-Zheng,et al."Discovery of Natural Potent HMG-CoA Reductase Degraders for Lowering Cholesterol".ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2023).

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