Discovery and Design of Novel Cyclic Peptides as Specific Inhibitors Targeting CCN2 and Disrupting CCN2/EGFR Interaction for Kidney Fibrosis Treatment

Kidney fibrosis is a serious consequence of chronic kidneydisease(CKD), and currently, there is no effective pharmacological treatmentavailable. Cellular communication network-2 (CCN2/CTGF) is an extracellularmatrix (ECM) protein that regulates the fibrotic process by activatingthe epidermal growth factor receptor (EGFR) signaling pathway. Weherein present the discovery and structure-activity relationshipstudy of novel peptides targeting CCN2 to develop potent and stablespecific inhibitors of the CCN2/EGFR interaction. Remarkably, the7-mer cyclic peptide OK2 exhibited potent activitiesto inhibit CCN2/EGFR-induced STAT3 phosphorylation and cellular ECMprotein synthesis. Subsequent in vivo studies demonstratedthat OK2 significantly alleviated renal fibrosis in aunilateral ureteral obstruction (UUO) mouse model. Moreover, thisstudy first revealed that the peptide candidate could efficientlyblock CCN2/EGFR interaction through binding to the CT domain of CCN2,providing a new alternative strategy for peptide-based targeting ofCCN2 and modulating CCN2/EGFR-mediated biological functions in kidneyfibrosis.