1. Academic Validation
  2. Design and Synthesis of Novel Ultralong-Acting Peptides as EDP-EBP Interaction Inhibitors for Pulmonary Fibrosis Treatment

Design and Synthesis of Novel Ultralong-Acting Peptides as EDP-EBP Interaction Inhibitors for Pulmonary Fibrosis Treatment

  • J Med Chem. 2024 Apr 25;67(8):6624-6637. doi: 10.1021/acs.jmedchem.4c00067.
Yixiang Wang 1 2 Fanghan Xue 1 Wei Cheng 1 Qian Zhao 1 Nazi Song 1 Zihan Shi 1 Han Liu 1 Yu Li 1 Qinglin Tang 3 Qi Liu 3 Yiqing Wang 2 4 Fangfang Zhang 5 Xianxing Jiang 1
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, China.
  • 2 The First School of Clinical Medicine & The First Hospital, Lanzhou University, Lanzhou, Gansu 730000, China.
  • 3 Shenzhen Turier Biotech. Co. Ltd, Shenzhen 518000, China.
  • 4 Gansu International Scientific and Technological Cooperation Base of Reproductive Medicine Transformation Application & Key Laboratory for Reproductive Medicine and Embryo of Gansu Province, Lanzhou University, Lanzhou, Gansu 730000, China.
  • 5 School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, China.
Abstract

The increased remodeling of the extracellular matrix (ECM) in pulmonary fibrosis (PF) generates bioactive ECM fragments called matricryptins, which include elastin-derived Peptides (EDPs). The interaction between EDPs and their receptors, including elastin-binding protein (EBP), plays a crucial role in exacerbating fibrosis. Here, we present LXJ-02 for the first time, a novel ultralong-acting inhibitor that disrupts the EDPs/EBP peptide-protein interaction, promoting macrophages to secrete matrix metalloproteinase-12 (MMP-12), and showing great promise as a stable peptide. MMP-12 has traditionally been implicated in promoting inflammation and fibrosis in various acute and chronic diseases. However, we reveal a novel role of LXJ-02 that activates the macrophage-MMP-12 axis to increase MMP-12 expression and degrade ECM components like elastin. This leads to the preventing of PF while also improving EDP-EBP interaction. LXJ-02 effectively reverses PF in mouse models with minimal side effects, holding great promise as an excellent therapeutic agent for lung fibrosis.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-P6183
    EDPs/EBP Inhibitor