DC646 Shows Promise as a Therapeutic Approach for MASH

Data published in Life Metabolism show that the novel cyclic peptide antagonist DC646—which specifically targets the intestinal farnesoid X receptor (FXR) and disrupts FXR-co-activator interactions—is a promising therapeutic approach for patients with metabolic dysfunction-associated steatohepatitis (MASH). The authors note their optimism that FXR antagonists can be a new approach to treating hepatitis-related conditions, but additional research is required to study the safety and benefits of this agent further.^1,2

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For this study, DC646, a cyclic peptide that specifically binds to the co-activator binding site of FXR, was used. It binds to the co-activator binding site of FXR, blocks co-activator recruitment, reduces intestinal ceramide production, and promotes the release of glucagon-like peptide-1 (GLP-1).²

FXR is a bile acid nuclear receptor that has a significant role in the regulation of bile acid and sterol metabolism. Bile acids are natural ligands of FXR, which bind to the ligand-binding pocket (LBP) within the ligand-binding domain (LBD) of FXR. This induces conformational changes that recruit co-activators, activating transcriptional activity. Current endogenous or synthetic FXR antagonists—such as glycoursodeoxycholic acid—target the LBP by competitively blocking the binding of FXR-activating bile acids (eg, chenodeoxycholic acid), therefore, inhibiting the activity of FXR.^1,2

Prior studies have confirmed that intestinal FXR antagonists can effectively improve metabolic disorders, such as MASH; however, traditional FXR antagonists are mostly indirect regulators of FXR activity; therefore, their inhibition is often influenced by the proportion of bile acids with antagonistic and agonistic properties in the bile acid pool, contributing to weak and unstable effects. Alternatively, cyclic peptides combine characteristics of both small molecules and proteins and have emerged as significant molecules for regulating protein-protein interactions (PPIs). Studies have confirmed their efficacy in influencing metabolism and gut microbiota composition, as well as their ability to exhibit strong lipophilicity, making them less likely to infiltrate the intestinal epithelium. For these reasons, developing FXR-antagonistic cyclic peptides holds promise for creating intestinally targeted FXR antagonists, according to the authors.^1,2

In the current study¹, the authors used an AlphaScreen assay to identify a series of tryptophan-based cyclic peptide compounds with FXR-antagonistic activity, specifically those modified with a C4-position morpholine group. DC646 was identified to be the most potent FXR antagonist, with an inhibition rate exceeding 70%. Additionally, the authors designed and synthesized a biotinylated cyclic peptide probe, BIOTIN-DC646, to validate its role as a PPI inhibitor using co-immunoprecipitation experiments.¹

In vivo assessments demonstrated that DC646 selectively inhibited FXR signaling in the intestines of model mice with MASH without affecting hepatic FXR signaling. Tissue distribution studies further confirmed these strong intestine-targeting properties of DC646. Additionally, compared with other endogenous intestinal FXR antagonists, DC646 showed strong efficacy in alleviating hepatic lipid metabolism disorders, inflammation, and fibrosis.^1,2

Finally, to further investigate DC646 effects on MASH, the authors conducted pharmacodynamic evaluations in Fxr-deficient mouse models. The reduction in alanine aminotransferase levels and anti-steatosis effects observed in wild-type mice treated with DC646 were not observed in Fxr-deficient mice, confirming that the effects on steatosis and disease mitigation are slowed through its specific targeting of intestinal FXR. DC646 was also shown to impede intestinal FXR, reduce intestinal ceramide production, and induce GLP-1 expression in high-fat diet (HFD) mouse models. The agent also had a tolerable dose that was about 20 times higher than the minimum effective dose (200 mg/kg), indicating a favorable safety profile.^1,2

This approach holds potential for MASH treatment while maintaining a good safety profile. Further research, including in-human studies, will be needed to confirm the safety and benefits of DC646 in MASH.²

REFERENCES

1. Yazhou Li, Tingying Jiao, Xi Cheng, et al. Development of cyclopeptide inhibitors specifically disrupting FXR-coactivator interaction in the intestine as a novel therapeutic strategy for MASH. Life Metabolism. Published February 8, 2025. doi:10.1093/lifemeta/loaf004

2. Higher Education Press. FXR cyclic peptide antagonists as a novel strategy for MASH treatment. News release. March 14, 2025. Accessed March 14, 2025. https://www.eurekalert.org/news-releases/1076942