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

Abstract

Kidney fibrosis is a serious consequence of chronic kidney disease (CKD), and currently, there is no effective pharmacological treatment available. Cellular communication network-2 (CCN2/CTGF) is an extracellular matrix (ECM) protein that regulates the fibrotic process by activating the epidermal growth factor receptor (EGFR) signaling pathway. We herein present the discovery and structure-activity relationship study of novel peptides targeting CCN2 to develop potent and stable specific inhibitors of the CCN2/EGFR interaction. Remarkably, the 7-mer cyclic peptide <b>OK2</b> exhibited potent activities to inhibit CCN2/EGFR-induced STAT3 phosphorylation and cellular ECM protein synthesis. Subsequent <i>in vivo</i> studies demonstrated that <b>OK2</b> significantly alleviated renal fibrosis in a unilateral ureteral obstruction (UUO) mouse model. Moreover, this study first revealed that the peptide candidate could efficiently block CCN2/EGFR interaction through binding to the CT domain of CCN2, providing a new alternative strategy for peptide-based targeting of CCN2 and modulating CCN2/EGFR-mediated biological functions in kidney fibrosis.