Design and Discovery of Novel Cyclic Peptides as EDPs-EBP Interaction Inhibitors for the Treatment of Liver Fibrosis.

Liver fibrosis is the undesirable result of excessive deposition of the extracellular matrix (ECM), and elastin is known as one of the key ECM components. Under specific pathological conditions, elastin undergoes degradation to produce elastin-derived peptides (EDPs), which bind to elastin-binding protein (EBP) to activate corresponding signal pathways, thus accelerating fibrosis progression. Herein, we describe the discovery of novel cyclic peptides that function as potent and stable inhibitors to interfere with the peptide-protein interaction between EDPs and EBP. Remarkably, CXJ-2 exhibited potent activities to inhibit the PI3K/ERK pathway and decrease hepatic stellate cell proliferation and migration. The subsequent in vivo study demonstrated that CXJ-2 possessed potent antifibrotic efficacy in ameliorating CCl4-induced liver fibrosis. This work provides a successful pharmacological strategy for the development of novel inhibitors of EDPs-EBP interaction, which sheds new light on how cyclic peptides disrupt peptide-protein interaction and may also provide new structure-oriented therapeutic candidates in liver fibrosis.

Citation

Nazi Song, Haonan Li, Qinglin Tang, Suijia Luo, Zihan Shi, Qian Zhao, Runkai Li, Yili Chen, Xiaoqing Cai, Xianxing Jiang. Design and Discovery of Novel Cyclic Peptides as EDPs-EBP Interaction Inhibitors for the Treatment of Liver Fibrosis. Journal of medicinal chemistry. 2023 Apr 13;66(7):4689-4702

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PMID: 36938613

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