Design and discovery of novel cyclic peptides as TSP1-CD36 interaction inhibitors for intestinal fibrosis treatment

  • Bioorg Chem. 2025 Aug:163:108667. doi: 10.1016/j.bioorg.2025.108667.
Wen Zhang  1 ,  Liang Qi  2 ,  Wei Cheng  2 ,  Xianggui Wang  2 ,  Yujie Hong  2 ,  Rui Dong  3 ,  Weiqi Yuan  4 ,  Dekui Zhang  5
Affiliations
  • 1. The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730000, China.
  • 2. State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
  • 3. State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610021, China. Electronic address: [email protected].
  • 4. State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610021, China; Sichuan Greentech Bioscience Co., Ltd, Meishan 610041, China. Electronic address: [email protected].
  • 5. The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730000, China. Electronic address: [email protected].
PMID: 40483936 DOI: 10.1016/j.bioorg.2025.108667
Abstract

Intestinal fibrosis is a refractory complication of inflammatory bowel disease (IBD), arising from recurrent intestinal inflammation and excessive wound healing. Repeated strictures can lead to intestinal obstruction, with three-quarters of patients with strictures eventually requiring surgery, which severely impacts their quality of life. Thrombospondin-1 (TSP1) is a matricellular protein that regulates tissue fibrosis by binding to its cell membrane receptor, CD36, and activating transforming growth factor β (TGF-β). In this study, based on molecular docking simulations, overlapping peptide libraries, and introducing non-natural amino acid modifications, we designed a cyclic peptide derived from the structure of CD36 (93-110), 19A8.8, which potently inhibited the epithelial-mesenchymal transition (EMT) of IEC-6 cells and reduced extracellular matrix protein deposition by disrupting the TSP1-CD36 interaction. In both in vitro and in vivo intestinal fibrosis models, 19A8.8 was shown to alleviate intestinal fibrosis by suppressing SMAD3 phosphorylation and blocking the TGF-β/SMAD3 signaling pathway. This study is the first to identify a novel therapeutic target for intestinal fibrosis and proposes the cyclic peptide 19A8.8 as a potential candidate drug for its treatment.

Keywords
Cyclic peptide; Inflammatory bowel disease; Intestinal fibrosis; Smad3.
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