2. Academic Validation
  3. Development of a leucine aminopeptidase-activatable co-prodrug from CDDO-Me and ligustrazine for synergistic treatment of liver injury

Development of a leucine aminopeptidase-activatable co-prodrug from CDDO-Me and ligustrazine for synergistic treatment of liver injury

  • Bioorg Chem. 2025 Nov:166:109177. doi: 10.1016/j.bioorg.2025.109177.
Fang Chen 1,  Jiaxin Zheng 2,  Ke Xu 1,  Hao Lu 3,  Dongwei Liu 1,  Xiao Liu 3,  Lei Wang 4,  Xing Su 5,  Yong Ling 6
Affiliations

Affiliations

  • 1 Department of Pharmacy, Dafeng People's Hospital, Yancheng 224000, China; School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong Key Laboratory of Small Molecular Drug Innovation, Nantong University, Nantong 226001, China.
  • 2 School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong Key Laboratory of Small Molecular Drug Innovation, Nantong University, Nantong 226001, China.
  • 3 School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong Key Laboratory of Small Molecular Drug Innovation, Nantong University, Nantong 226001, China; Department of Pharmacy, Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong 226001, China.
  • 4 Department of Pharmacy, Dafeng People's Hospital, Yancheng 224000, China; School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong Key Laboratory of Small Molecular Drug Innovation, Nantong University, Nantong 226001, China. Electronic address: wanglei2111@ntu.edu.cn.
  • 5 School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong Key Laboratory of Small Molecular Drug Innovation, Nantong University, Nantong 226001, China; Department of Pharmacy, Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong 226001, China. Electronic address: suxing2627@163.com.
  • 6 Department of Pharmacy, Dafeng People's Hospital, Yancheng 224000, China; School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong Key Laboratory of Small Molecular Drug Innovation, Nantong University, Nantong 226001, China. Electronic address: lyyy111@sina.com.
PMID: 41175723 DOI: 10.1016/j.bioorg.2025.109177
Abstract

Liver injury is pathological basis of various hepatic diseases, including different kinds of hepatitis and even liver Cancer. Hence, we designed and synthesized a co-prodrug CHL from CDDO-Me and ligustrazine (HMP) which can be specifically activated by leucine Aminopeptidase (LAP) and release >90 % two active drugs (CDDO-Me and HMP) to exert its multiple anti-inflammatory activities in liver injury models by reducing intracellular Reactive Oxygen Species (ROS), mitochondrial damage, and Apoptosis. Excitingly, CHL not only exhibited more significant anti-injury effects on liver both in vitro and in vivo of CCl4-simulated models compared to the parent drugs combination therapy, but also significantly induced the expression of Nrf2-dependent antioxidant genes (HO-1 and NQO1), increasing them by 4.2- and 5.5-fold, respectively. Furthermore, CHL reduced p-p65 expression by 5-fold, indicating its effective inhibition of NF-κB transcriptional activity and thereby alleviating inflammatory responses. Therefore, the LAP-activable co-prodrug CHL holds promising potential as a candidate for the synergistic treatment of liver injury.

Keywords

Antiinflammation; CDDO-me; Co-prodrug; Ligustrazine (HMP); Liver injury.

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