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

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.

肺纤维化（pulmonary fibrosis, PF）中细胞外基质（extracellular matrix, ECM）的重塑增强，可产生一类具有生物活性的ECM片段，称为基质隐肽（matricryptins），其中包含弹性蛋白衍生肽（elastin-derived peptides, EDPs）。弹性蛋白衍生肽（EDPs）与其受体（包括弹性蛋白结合蛋白（elastin-binding protein, EBP））之间的相互作用，在纤维化恶化过程中发挥关键调控作用。本研究首次报道了LXJ-02——一种新型超长效抑制剂，可阻断EDPs与EBP之间的肽-蛋白相互作用，促进巨噬细胞分泌基质金属蛋白酶-12（matrix metalloproteinase-12, MMP-12），且作为稳定肽类展现出良好的应用前景。既往研究认为，基质金属蛋白酶-12（MMP-12）在多种急慢性疾病中均与炎症反应及纤维化进程密切相关。但本研究揭示了LXJ-02的全新作用机制：其通过激活巨噬细胞-MMP-12轴，上调MMP-12的表达并降解弹性蛋白等ECM组分，由此可阻断肺纤维化进程，同时改善EDPs与EBP的异常相互作用。LXJ-02可在小鼠肺纤维化模型中有效逆转病变，且副作用极小，作为治疗肺纤维化的优秀候选治疗药物具有巨大的应用潜力。