Article

WZ66, a novel acetyl-CoA carboxylase inhibitor, alleviates nonalcoholic steatohepatitis (NASH) in mice

Authors: Ying-sheng Gao1, Min-yi Qian1,2, Qiang-qiang Wei3, Xu-bin Duan1, Shi-lei Wang4, Hai-yang Hu5, Jun Liu1, Chu-yue Pan1, Shuo-quan Zhang1, Lian-wen Qi6, Jin-pei Zhou7, Hui-bin Zhang2, Li-rui Wang1
1 School of Basic Medicine and Clinical Pharmacy, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
2 College of pharmacy and chemistry, Dali University, Dali 671003, China
3 Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
4 School of Traditional Chinese Pharmacy, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
5 School of life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
6 Clinical Metabolomics Center, China Pharmaceutical University, Nanjing 211198, China
7 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China
Correspondence to: Hui-bin Zhang: zhanghb80@cpu.edu.cn, Li-rui Wang: wanglirui@cpu.edu.cn,
DOI: 10.1038/s41401-019-0310-0
Received: 18 June 2019
Accepted: 12 September 2019
Advance online: 23 October 2019

Abstract

The global prevalence of nonalcoholic steatohepatitis (NASH) increases incredibly. NASH ends up to advanced liver disease, which is highly threatening to human health. Currently, treatment of NASH is very limited. Acetyl-CoA carboxylases (ACC1/ACC2) are proved as effective drug targets for NASH. We aimed to develop novel ACC inhibitors and evaluate their therapeutic value for NASH prevention. ACC inhibitors were obtained through structure-based drug design, synthesized, screened from ACC enzymatic measurement platform and elucidated in cell culture-based assays and animal models. The lipidome and microbiome analysis were integrated to assess the effects of WZ66 on lipids profiles in liver and plasma as well as gut microbiota in the intestine. WZ66 was identified as a novel ACC1/2 inhibitor. It entered systemic circulation rapidly and could accumulate in liver. WZ66 alleviated NASH-related liver features including steatosis, Kupffer cells and hepatic stellate cells activation in diet-induced obese mice. The triglycerides (TGs) and other lipids including diglycerides (DGs), phosphatidylcholine (PC) and sphingomyelin (SM) were decreased in WZ66-treated mice as evidenced by lipidome analysis in livers. The lipids profiles in plasma were also altered with WZ66 treatment. Plasma TG were moderately increased, while the activation of SREBP1c was not detected. WZ66 also downregulated the abundance of Allobaculum, Mucispirillum and Prevotella genera as well as Mucispirillum schaedleri species in gut microbiota. WZ66 is an ideal lead compound and a potential drug candidate deserving further investigation in the therapeutics of NASH.
Keywords: nonalcoholic steatohepatitis; Acetyl-CoA carboxylase; WZ66; pharmacokinetics lipidome; gut microbiome

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