Discovery of Novel Cyclic Peptides as SMAD2–SMAD4 Interaction Inhibitors for the Treatment of Hepatic Fibrosis

Hepatic fibrosis, characterized by the excessive deposition of the extracellular matrix, represents a common consequence of various chronic liver disorders. However, no specific drugs are available for antifibrotic therapy to date. SMAD2 is phosphorylated by transforming growth factor-β and subsequently binds to SMAD4 to generate a heteromeric complex, which then translocates into the nucleus and aggravates liver fibrosis. Herein, based on molecular docking simulation and structure–activity relationship study, we report the discovery of a novel cyclic peptide CMF9 that targets SMAD2 and potently interferes with the SMAD2–SMAD4 interaction. The subsequent in vivo and in vitro pharmacological studies demonstrated that CMF9 dramatically suppressed hepatic stellate cells activation and collagen synthesis, alleviating CCl₄-induced hepatic inflammation and fibrosis. Overall, we first demonstrated that the novel cyclic peptide CMF9 could efficiently block the SMAD2–SMAD4 interaction via selectively inhibiting SMAD2 phosphorylation, providing a promising therapeutic strategy for targeting SMAD2 and an alternative candidate for the treatment of liver fibrosis.