Novel Jatrophane Diterpenoids from Euphorbia esula Promotes Lipid Clearance by Transcriptional Regulation of PCSK9
文献类型：期刊论文
| 作者 | Chen, Tong3,4; Hou, Aijun1,3; Guo, Pengju2,3; Peng, Shou2,3; Qin, Guoqing2,3; Ding, Aoxue2,3; Hu, Xianggang3,4; Duan, Yelin3,4; Chen, Jing3 ; Gong, Likun3
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2024-07-03 |
| 卷号 | 67期号:14页码:12055-12067 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.4c00779 |
| 通讯作者 | Chen, Jing(jingchen@simm.ac.cn) ; Gong, Likun(lkgong@simm.ac.cn) ; Xuan, Lijiang(ljxuan@simm.ac.cn) |
| 英文摘要 | PCSK9 has been recognized as an efficient target for hyperlipidemia and related cardiovascular/cerebrovascular diseases. However, PCSK9 inhibitors in the clinic are all biological products, and no small molecules are available yet. In the current work, we discovered that the crude extract of Euphorbia esula (E. esula) promoted LDL uptake in vitro and then obtained 8 new and 12 known jatrophane diterpenoids by activity-guided isolation. After summarized their structure-activity relationship of PCSK9 inhibition, we selected compound 11 (C11) with potent activity and high abundance to investigate its mechanism and in vivo efficacy. Mechanistically, C11 bound with HNF1 alpha to influence its nuclear distribution and subsequently inhibit PCSK9 transcription, thereby enhancing LDLR and promoting LDL uptake. Moreover, C11 demonstrated obvious lipid-lowering activity in HFD mouse model. In conclusion, we first revealed the novel application of E. esula in the discovery of a lipid-lowering candidate and highlighted the potential of C11 in the treatment of hyperlipidemia. |
| WOS关键词 | INHIBITORS |
| 资助项目 | State Key Laboratory of Drug Research[SIMM1601ZZ-03] ; Shanghai Municipal Science and Technology Major Project[TM202301L001] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001265522200001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/312252]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Chen, Jing; Gong, Likun; Xuan, Lijiang |
| 作者单位 | 1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 2.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China 3.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, 501 Haike Rd, Shanghai 201203, Peoples R China 4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Tong,Hou, Aijun,Guo, Pengju,et al. Novel Jatrophane Diterpenoids from Euphorbia esula Promotes Lipid Clearance by Transcriptional Regulation of PCSK9[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(14):12055-12067. |
| APA | Chen, Tong.,Hou, Aijun.,Guo, Pengju.,Peng, Shou.,Qin, Guoqing.,...&Xuan, Lijiang.(2024).Novel Jatrophane Diterpenoids from Euphorbia esula Promotes Lipid Clearance by Transcriptional Regulation of PCSK9.JOURNAL OF MEDICINAL CHEMISTRY,67(14),12055-12067. |
| MLA | Chen, Tong,et al."Novel Jatrophane Diterpenoids from Euphorbia esula Promotes Lipid Clearance by Transcriptional Regulation of PCSK9".JOURNAL OF MEDICINAL CHEMISTRY 67.14(2024):12055-12067. |
入库方式： OAI收割
来源：上海药物研究所
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