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

Liver fibrosis is a condition characterized by aberrant
proliferation
of connective tissue in the liver resulting from diverse etiological
factors. G protein-coupled receptor GPR55 has recently been identified
as a regulator of liver diseases. Herein, we report the discovery
of a cyclic peptide P1-1 that antagonizes GPR55 and suppresses collagen
secretion in hepatic stellate cells. The alanine scanning and docking
study was carried out to predict the binding mode and allowed for
further structural optimization of peptide antagonists for GPR55.
The subsequent in vivo study demonstrated that P1-1
ameliorates CCl4-induce and MCD-diet-induce acute liver
inflammation and fibrosis. Further study indicates that P1-1 reduces
reactive oxygen species (ROS) production, attenuates ER stress, and
inhibits mitochondria-associated hepatocyte apoptosis. In this work,
we provided the first successful example of antagonizing GPR55 for
liver inflammation and fibrosis, which validates GPR55 as a promising
target for the treatment of liver fibrosis and affords a high-potent
GPR55 antagonist P1-1 as a potential therapeutic candidate.