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

Autor: Su XZ; State Key Laboratory of Phytochemistry and Plant Resources in West China, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Kunming, 650201, China., Zhang LF; State Key Laboratory of Phytochemistry and Plant Resources in West China, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Kunming, 650201, China., Hu K; State Key Laboratory of Phytochemistry and Plant Resources in West China, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Kunming, 650201, China., An Y; Gene Editing Center, School of Life Science and Technology, ShanghaiTech University Shanghai 201210 (China)., Zhang QP; State Key Laboratory of Phytochemistry and Plant Resources in West China, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Kunming, 650201, China., Tang JW; State Key Laboratory of Phytochemistry and Plant Resources in West China, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Kunming, 650201, China., Yan BC; State Key Laboratory of Phytochemistry and Plant Resources in West China, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Kunming, 650201, China., Li XR; State Key Laboratory of Phytochemistry and Plant Resources in West China, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Kunming, 650201, China., Cai J; The Germplasm Bank of Wild Species, Kunming Institute of Botany, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Kunming, 650201, China., Li XN; State Key Laboratory of Phytochemistry and Plant Resources in West China, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Kunming, 650201, China., Sun HD; State Key Laboratory of Phytochemistry and Plant Resources in West China, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Kunming, 650201, China., Jiang SY; State Key Laboratory of Phytochemistry and Plant Resources in West China, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Kunming, 650201, China., Puno PT; State Key Laboratory of Phytochemistry and Plant Resources in West China, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Kunming, 650201, China.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2024 Feb 05; Vol. 63 (6), pp. e202313859. Date of Electronic Publication: 2023 Dec 20.
DOI: 10.1002/anie.202313859
Abstrakt: 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.
(© 2023 Wiley-VCH GmbH.)
Databáze: MEDLINE
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