2. Academic Validation
  3. 7-aminocephalosporanic acid, a novel HSP90β inhibitor, attenuates HFD-induced hepatic steatosis

7-aminocephalosporanic acid, a novel HSP90β inhibitor, attenuates HFD-induced hepatic steatosis

  • Biochem Biophys Res Commun. 2022 Sep 24:622:184-191. doi: 10.1016/j.bbrc.2022.07.033.
Weitao Zhang 1,  Hanyue Xue 2,  Chen Zhou 3,  Zuguo Zheng 2,  Mingming Xing 2,  Hang Chu 2,  Ping Li 2,  Naixia Zhang 3,  Yongjun Dang 4,  Xiaojun Xu 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, Nanjing, Jiangsu, China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, 210009, Nanjing, Jiangsu, China.
  • 2 State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, Nanjing, Jiangsu, China.
  • 3 Department of Analytical Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China; University of the Chinese Academy of Sciences, 19A Yuquan Road, Beijing, 100049, China.
  • 4 Center for Novel Target and Therapeutic Intervention, Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, China.
  • 5 State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, Nanjing, Jiangsu, China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, 210009, Nanjing, Jiangsu, China. Electronic address: xiaojunxu@cpu.edu.cn.
PMID: 35932530 DOI: 10.1016/j.bbrc.2022.07.033
Abstract

Hepatic steatosis is one of the most important causes of liver disease worldwide. Heat shock protein 90 (HSP90) is essential for numerous client proteins. Recently, more attention was focused on increased HSP90 levels in hepatic steatosis, especially HSP90β. Thus, great efforts have been made to develop HSP90β inhibitors, and most natural inhibitors are derived from Microorganisms. In this study, using microarray chips and surface pasmon resonance (SPR) technology, we screened 189 Antibiotics in order to obtain an inhibitor directly binding to the non-N-terminal domain of HSP90β. Finally, we discovered an Antibiotic, 7-aminocephalosporanic acid (7ACA), with a KD value of 6.201 μM between 7ACA and non-N-terminal domain of HSP90β. Besides, 7ACA was predicted to interact with the middle domain (MD) of HSP90β. In HepG2 cells, we found that 7ACA reduced cellular total Cholesterol (TC) and triglyceride (TG) by decreasing sterol regulatory element-binding proteins (SREBPs). In HFD fed mice, administration of 7ACA (5, 10, and 25 mg kg-1 d-1, ig, for 12 weeks) dose-dependently decreased serum TC and TG and played an important role in protecting liver and adipose tissue from lipid accumulation. In conclusion, our study demonstrated that Antibiotic 7ACA, as an HSP90β middle domain inhibitor, was promising for the development of lipid-lowering drugs.

Keywords

7-aminocephalosporanic acid; HSP90β; NAFLD; SPR; de novo lipogenesis.

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