2. Academic Validation
  3. Development of cyclopeptide inhibitors specifically disrupting FXR-coactivator interaction in the intestine as a novel therapeutic strategy for MASH

Development of cyclopeptide inhibitors specifically disrupting FXR-coactivator interaction in the intestine as a novel therapeutic strategy for MASH

  • Life Metab. 2025 Feb 8;4(2):loaf004. doi: 10.1093/lifemeta/loaf004.
Yazhou Li 1 2,  Tingying Jiao 2 3,  Xi Cheng 1 2,  Lu Liu 2,  Mengjiao Zhang 4,  Jian Li 2,  Jue Wang 5,  Shulei Hu 2,  Cuina Li 2,  Tao Yu 2,  Yameng Liu 2,  Yangtai Li 6,  Yu Zhang 2 7,  Chuying Sun 4,  Jina Sun 2 7,  Jiang Wang 2 7,  Cen Xie 2 4,  Hong Liu 1 2 4
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310024, China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 State Key Laboratory of Genetic Engineering, School of Life Sciences, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Metabonomics and Systems Biology Laboratory at Shanghai International Centre for Molecular Phenomics, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China.
  • 5 Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 6 School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, China.
  • 7 Lingang Laboratory, Shanghai 200031, China.
PMID: 40225300 DOI: 10.1093/lifemeta/loaf004
Abstract

Intestinal farnesoid X receptor (FXR) antagonists have been proven to be efficacious in ameliorating metabolic diseases, particularly for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). All the reported FXR antagonists target to the ligand-binding pocket (LBP) of the receptor, whereas antagonist acting on the non-LBP site of nuclear receptor (NR) is conceived as a promising strategy to discover novel FXR antagonist. Here, we have postulated the hypothesis of antagonizing FXR by disrupting the interaction between FXR and coactivators, and have successfully developed a series of macrocyclic peptides as FXR antagonists based on this premise. The cyclopeptide DC646 not only exhibits potent inhibitory activity of FXR, but also demonstrates a high degree of selectivity towards Other NRs. Moreover, cyclopeptide DC646 has high potential therapeutic benefit for the treatment of MASH in an intestinal FXR-dependent manner, along with a commendable safety profile. Mechanistically, distinct from Other known FXR antagonists, cyclopeptide DC646 specifically binds to the coactivator binding site of FXR, which can block the coactivator recruitment, reducing the circulation of intestine-derived ceramides to the liver, and promoting the release of glucagon-like peptide-1 (GLP-1). Overall, we identify a novel cyclopeptide that targets FXR-coactivator interaction, paving the way for a new approach to treating MASH with FXR antagonists.

Keywords

FXR antagonists; cyclopeptide; intestine-targeted drugs; metabolic dysfunction-associated steatohepatitis; protein–protein interactions.

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