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 C11 exhibited the highest potency, binding directly to Collagen
I and effectively disrupting its interaction with Lumican. In vivo studies demonstrated that peptide C11 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.