Design and Discovery of Novel Cyclic Peptides as EDPs–EBP Interaction Inhibitors for the Treatment of Liver Fibrosis

Liver fibrosis is the undesirable result of excessive
deposition
of the extracellular matrix (ECM), and elastin is known as one of
the key ECM components. Under specific pathological conditions, elastin
undergoes degradation to produce elastin-derived peptides (EDPs),
which bind to elastin-binding protein (EBP) to activate corresponding
signal pathways, thus accelerating fibrosis progression. Herein, we
describe the discovery of novel cyclic peptides that function as potent
and stable inhibitors to interfere with the peptide–protein
interaction between EDPs and EBP. Remarkably, CXJ-2 exhibited potent activities to inhibit
the PI3K/ERK pathway and decrease hepatic stellate cell proliferation
and migration. The subsequent in vivo study demonstrated that CXJ-2 possessed potent
antifibrotic efficacy in ameliorating CCl4-induced liver
fibrosis. This work provides a successful pharmacological strategy
for the development of novel inhibitors of EDPs–EBP interaction,
which sheds new light on how cyclic peptides disrupt peptide–protein
interaction and may also provide new structure-oriented therapeutic
candidates in liver fibrosis.