Structure-Based Development of a Novel Macrocyclic Peptide to Disrupt the Lumican–Collagen I Interaction in Liver Fibrosis

Liver fibrosis is a common and severe hepatic disorder characterized by the excessive accumulation of Collagen I. Lumican, an extracellular matrix protein, plays a critical role in collagen fibril assembly and contributes to progression. However, macrocyclic peptide-based inhibitors of this interaction remain largely unexplored. Herein, we report the discovery and structure-activity relationship of novel macrocyclic peptides that act as potent and stable inhibitors of the Lumican-Collagen I interaction. Among these, peptide <b>C11</b> exhibited the highest potency, binding directly to Collagen I and effectively disrupting its interaction with Lumican. <i>In vivo</i> studies demonstrated that peptide <b>C11</b> significantly alleviated CCl₄-induced liver fibrosis by reducing inflammatory infiltration and collagen deposition. These findings suggest that targeting the Lumican-Collagen I interaction represents a promising therapeutic strategy for antifibrotic treatment, particularly through the disruption of collagen maturation and deposition.