2. Academic Validation
  3. Novel Jatrophane Diterpenoids from Euphorbia esul a Promotes Lipid Clearance by Transcriptional Regulation of PCSK9

Novel Jatrophane Diterpenoids from Euphorbia esul a Promotes Lipid Clearance by Transcriptional Regulation of PCSK9

  • J Med Chem. 2024 Jul 3. doi: 10.1021/acs.jmedchem.4c00779.
Tong Chen 1 2,  Aijun Hou 2 3,  Pengju Guo 2 4,  Shou Peng 2 4,  Guoqing Qin 2 4,  Aoxue Ding 2 4,  Xianggang Hu 1 2,  Yelin Duan 1 2,  Jing Chen 2,  Likun Gong 2,  Lijiang Xuan 1 2
Affiliations

Affiliations

  • 1 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, People's Republic of China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, People's Republic of China.
  • 3 University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, People's Republic of China.
  • 4 School of Pharmacy, Fudan University, Shanghai 201203, PR China.
PMID: 38959380 DOI: 10.1021/acs.jmedchem.4c00779
Abstract

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 HNF1α 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.

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