2. Academic Validation
  3. Water-soluble and predictable-release triptolide prodrugs block bleomycin-induced pulmonary fibrosis in mice

Water-soluble and predictable-release triptolide prodrugs block bleomycin-induced pulmonary fibrosis in mice

  • Eur J Med Chem. 2024 Sep 6:279:116839. doi: 10.1016/j.ejmech.2024.116839.
Yuhan Chen 1,  Meiyu Liang 1,  Wen Li 1,  Zhiming Yang 1,  Xingting Yan 2,  Liuying Wu 1,  Qin Yu 1,  Yubai Chen 2,  Yong Chen 1,  Yan Xu 3,  Wei Song 4,  Zhihong Peng 5
Affiliations

Affiliations

  • 1 College of Health Science and Engineering, National & Local Joint Engineering Research Center of High-Throughput Drug Screening Technology, Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, Hubei University, Wuhan, 430062, China.
  • 2 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350004, China.
  • 3 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350004, China. Electronic address: xyan_2014@fjmu.edu.cn.
  • 4 College of Health Science and Engineering, National & Local Joint Engineering Research Center of High-Throughput Drug Screening Technology, Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, Hubei University, Wuhan, 430062, China. Electronic address: songwei_83@hubu.edu.cn.
  • 5 College of Health Science and Engineering, National & Local Joint Engineering Research Center of High-Throughput Drug Screening Technology, Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, Hubei University, Wuhan, 430062, China. Electronic address: zhihongpeng@hubu.edu.cn.
PMID: 39265250 DOI: 10.1016/j.ejmech.2024.116839
Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive respiratory disease with no known cause. It is characterized by widespread inflammation and structural abnormalities in the alveoli of the lungs, ultimately leading to the development of pulmonary fibrosis. Triptolide (TP), an epoxy-diterpene lactone compound known for its potent anti-inflammatory and antifibrotic effects, was limited clinical use due to poor water solubility and side effects. Two soluble TP prodrugs (PG490-88 and Minnelide) have entered clinical research. However, their activities are based on Enzyme metabolism, which is influenced by species-specific differences. In this study, we present water-soluble TP derivatives synthesized by introducing ethylenediamine carbamate groups (TP-DEAs) at the 14-hydroxy position. The introduced groups were found to spontaneously convert into the parent drug through enzyme-independent metabolic conversion. The water solubility and stability of the compounds were examined in vitro. Notably, TP-DEA2 exhibited high water solubility (30.8 mg/mL), exceeding TP solubility by more than 1181-fold. In vitro, TP-DEA2 converted to TP autonomously without the involvement of Enzymes. In addition, TP-DEA2 can inhibit the expression of a disintegrin and metalloproteinase 10 (ADAM 10) induced by TGF-β1 and reduce the secretion of a-SMA in fibroblasts. In vivo, TP-DEA2 transformed into TP, effectively inhibiting fibrosis in the bleomycin group without observed toxicity. Importantly, positive outcomes when administering TP-DEA2 at a later stage post-bleomycin exposure suggest its potential role in treating IPF.

Keywords

A disintegrin and metalloproteinase 10; Idiopathic pulmonary fibrosis; TP-DEA2; Triptolide; Water-soluble.

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