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 OK2 exhibited potent activities to inhibit CCN2/EGFR-induced STAT3 phosphorylation and cellular ECM protein synthesis. Subsequent in vivo studies demonstrated that OK2 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.

Design and Synthesis of Novel Ultralong-Acting Peptides as EDP-EBP Interaction Inhibitors for Pulmonary Fibrosis Treatment

“…However, the application of this natural peptide in fibrotic diseases has been limited due to its high instability and poor half-life ( T 1/2 = 0.098 h). Inspired by our recent research efforts on the design of functional peptide skeletons, structure–activity relationships, and pharmacological mechanisms in the field of fibrotic diseases, ,,− we present here the design and discovery of a new library of ultralong-acting peptides as antagonists targeting elastin-binding proteins for the treatment of PF ( T 1/2 = 33.0 h). The observed prolongation of plasma half-life is likely due to the increasing length of fatty acid chains .…”

Discovery of Novel Peptide Antagonists Targeting GPR55 for Liver Inflammation and Fibrosis

“…Our research group is dedicated to discovering peptide drugs for the treatment of fibrotic diseases. Therefore, we have developed peptide drugs targeting GPR55, a recently identified target that affects liver fibrosis. − …”