Work

Design, molecular characterization and therapeutic investigation of a novel CCR8 peptide antagonist that attenuates acute liver injury by inhibiting infiltration and activation of macrophages

Year: 2025

Type: article

Abstract: During liver injury, intrahepatic macrophage compartment is augmented by circulating monocytes that infiltrate the liver driven by C–C motif chemokine ligand/C–C motif chemokine receptor (CCL/CCR) axis including CCL1‒CCR8 axis, thereby contributing to liver inflammation. Numerous small molecular receptor antagonists , including R243, have been developed for targeting CCR8; however, these agents face challenges in clinical translation, potentially attributed to their poor pharmacokinetic profiles, lack of target specificity, and potential adverse effects . In this study, we designed four CCR8 antagonizing peptides (AP8i-AP8iv) and performed molecular characterization in silico and therapeutic investigation in vitro and in vivo . Based on in silico docking, molecular dynamic simulation using homology build model and in-vitro (competitive) binding studies, AP8ii (YEWRFYHG) evidenced highly favorable and selective interactions at the CCR8-active site. AP8ii inhibited CCL1-driven chemotaxis and LPS/IFN γ -induced pro-inflammatory activation of monocytes-macrophages in vitro . In a CCl 4 -induced acute liver injury mouse model, AP8ii treatment decreased intrahepatic infiltration of circulating monocytes . Moreover, AP8ii reduced liver inflammation, as indicated by decreased F4/80, IL6 and iNOS expression, diminished ALT levels, and attenuated fibrosis , as indicated by reduced collagen-I expression. In conclusion, we report a novel CCR8-antagonizing peptide that inhibited CCL1-driven intrahepatic monocytes infiltration and differentiation into pro-inflammatory phenotype, consequently ameliorating liver inflammation and fibrogenesis in an acute liver injury mouse model.

Source: Acta Pharmaceutica Sinica B

DOI: 10.1016/j.apsb.2025.02.018