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
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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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