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Discovery of Novel Peptide Antagonists Targeting GPR55 for Liver Inflammation and Fibrosis
Zihan Shi1, Xianyan Liu1, Shuohan Wu1
1State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Abstract:
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.
Insights
Researchers discovered a new peptide, P1-1, that blocks G protein-coupled receptor GPR55. This peptide shows potential in treating liver fibrosis by reducing inflammation and cell damage.
Area of Science:
- Hepatology
- Pharmacology
- Molecular Biology
Background:
- Liver fibrosis involves excessive connective tissue growth in the liver.
- G protein-coupled receptor GPR55 is implicated in liver disease progression.
- Targeting GPR55 presents a potential therapeutic strategy for liver conditions.
Purpose of the Study:
- To identify and characterize a novel GPR55 antagonist.
- To evaluate the therapeutic potential of the antagonist in liver fibrosis models.
- To elucidate the mechanisms underlying the antagonist's effects on liver cells.
Main Methods:
- Discovery and structural optimization of cyclic peptide P1-1.
- In vitro studies on hepatic stellate cells to assess collagen secretion.
- In vivo studies using carbon tetrachloride (CCl4) and methionine- and choline-deficient (MCD) diet models of liver fibrosis.
Main Results:
- Peptide P1-1 effectively antagonizes GPR55 and reduces collagen secretion.
- P1-1 ameliorates liver inflammation and fibrosis in vivo.
- P1-1 mitigates oxidative stress, ER stress, and hepatocyte apoptosis.
Conclusions:
- GPR55 is a viable therapeutic target for liver inflammation and fibrosis.
- P1-1 is a potent GPR55 antagonist with therapeutic potential for liver fibrosis.
- This study provides a novel therapeutic candidate for treating liver diseases.
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