2. Academic Validation
  3. Discovery and characterization of novel ATP citrate lyase inhibitors from Acanthopanax senticosus (Rupr. & Maxim.) Harms

Discovery and characterization of novel ATP citrate lyase inhibitors from Acanthopanax senticosus (Rupr. & Maxim.) Harms

  • Fitoterapia. 2024 Apr 9:175:105956. doi: 10.1016/j.fitote.2024.105956.
Pan Wang 1,  Xiujie Guo 2,  Tao Hou 1,  Fengbin Luo 1,  Miao Li 3,  Xiaoyu Wang 4,  Jie Zhang 4,  Jixia Wang 5,  Chaoran Wang 6,  Xinmiao Liang 1
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
  • 2 CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; Zhejiang Acchrom Technologies Co.Ltd., Wenling 317503, China.
  • 3 Heilongjiang Provincial Drug Audit and Inspection Center, Harbin 150090, China.
  • 4 Heilongjiang Wusuli River Pharmaceutical Co.Ltd., Hulin 158417, China.
  • 5 CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China. Electronic address: jxwang@dicp.ac.cn.
  • 6 CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China. Electronic address: wcrpj_505@dicp.ac.cn.
PMID: 38604261 DOI: 10.1016/j.fitote.2024.105956
Abstract

ATP Citrate Lyase (ACLY) is a key Enzyme in glucolipid metabolism, and abnormally high expression of ACLY occurs in many diseases, including cancers, dyslipidemia and cardiovascular diseases. ACLY inhibitors are prospective treatments for these diseases. However, the scaffolds of ACLY inhibitors are insufficient with weak activity. The discovery of inhibitors with structural novelty and high activity continues to be a research hotpot. Acanthopanax senticosus (Rupr. & Maxim.) Harms is used for Cardiovascular Disease treatment, from which no ACLY inhibitors have ever been found. In this work, we discovered three novel ACLY inhibitors, and the most potent one was isochlorogenic acid C (ICC) with an IC50 value of 0.14 ± 0.04 μM. We found dicaffeoylquinic acids with ortho-dihydroxyphenyl groups were important features for inhibition by studying ten phenolic acids. We further investigated interactions between the highly active compound ICC and ACLY. Thermal shift assay revealed that ICC could directly bind to ACLY and improve its stability in the heating process. Enzymatic kinetic studies indicated ICC was a noncompetitive inhibitor of ACLY. Our work discovered novel ACLY inhibitors, provided valuable structure-activity patterns and deepened knowledge on the interactions between this targe tand its inhibitors.

Keywords

ACLY inhibitor; Acanthopanax senticosus (Rupr. & maxim.) harms; Natural products; Structure–activity relationship.

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