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Design, synthesis, and characterization of species-independent h/mGPR35 agonists for MAFLD/MASH
Hui Wen1, Junxiang Cheng1, Zhiwei Wang1
1Jiangxi Provincial Key Laboratory for Pharmacodynamic Material Basis of Traditional Chinese Medicine, Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China.
Abstract:
G protein-coupled receptor 35 (GPR35) has emerged as a potential therapeutic target for metabolic dysfunction-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatohepatitis (MASH). However, the sequence identity between human and mouse GPR35 is only 72%, which severely limits the development of species-independent active ligands for GPR35 and consequently hinders pharmacological studies targeting GPR35 in MAFLD/MASH. In this work, a series of novel GPR35 agonists based on the coumarin scaffold were developed, exhibiting low species differences between hGPR35 and mGPR35. Some of these agonists demonstrated low nanomolar potency, such as compound 6l (hEC50 = 30 nM, mEC50 = 21 nM) and compound 9f (hEC50 = 12 nM, mEC50 = 2 nM). The key binding sites of 6l and 9f with the h/mGPR35 receptor were further identified, respectively. Both compounds exhibited excellent lipid-lowering effects in in vitro and in vivo models. In a high-fat diet-induced mouse model of MASH, 6l and 9f significantly alleviated key pathological drivers of disease progression, including hepatic steatosis, lipid metabolism disorders, liver inflammation and fibrosis. Collectively, this study provides a class of novel agonists with high potency and low species differences for h/mGPR35, laying a foundation for further exploration of the pharmacological relationship between GPR35 and MAFLD/MASH.
Insights
Researchers developed novel G protein-coupled receptor 35 (GPR35) agonists to treat metabolic dysfunction-associated steatohepatitis (MASH). These potent compounds show minimal species differences, effectively reducing liver fat and inflammation in MASH models.
Area of Science:
- Pharmacology
- Hepatology
- Medicinal Chemistry
Background:
- G protein-coupled receptor 35 (GPR35) is a potential therapeutic target for metabolic dysfunction-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatohepatitis (MASH).
- Limited sequence identity (72%) between human and mouse GPR35 hinders the development of species-independent ligands, impeding pharmacological research.
Purpose of the Study:
- To develop novel GPR35 agonists with low species differences for targeting MAFLD/MASH.
- To evaluate the potency and efficacy of these agonists in preclinical models.
Main Methods:
- Design and synthesis of novel coumarin-based GPR35 agonists.
- Assessment of agonist potency against human (hGPR35) and mouse (mGPR35) receptors.
- In vitro and in vivo studies to evaluate lipid-lowering effects and MASH pathology.
- Identification of key binding sites for potent agonists.
Main Results:
- Several novel GPR35 agonists were identified, exhibiting low species differences.
- Compounds 6l and 9f demonstrated high potency (low nanomolar EC50 values) against both hGPR35 and mGPR35.
- These agonists showed significant lipid-lowering effects in vitro and in vivo.
- Compounds 6l and 9f effectively ameliorated hepatic steatosis, lipid metabolism disorders, inflammation, and fibrosis in a MASH mouse model.
Conclusions:
- A new class of potent GPR35 agonists with minimal species differences was successfully developed.
- These agonists hold promise for treating MAFLD/MASH by addressing key pathological drivers.
- The findings provide a foundation for further GPR35-targeted drug discovery for liver diseases.
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