Simplified Peptide That Blocks the Relaxin-3 Appetite Receptor Reduces Food Intake in Rats
A novel 14-residue stapled peptide antagonist targeting the RXFP3 receptor was 12× more stable than existing antagonists and successfully blocked feeding behavior in rats.
Quick Facts
What This Study Found
The researchers designed H3B10-22R-(13/17αF), a 14-residue single-chain stapled peptide that acts as a potent and selective RXFP3 antagonist. Compared to the previous best RXFP3 antagonist (H3B1-22R):
- 12-fold improved serum stability
- Enhanced helical structure and antagonist potency
- High RXFP3 selectivity and binding affinity
- Significantly inhibited RXFP3 agonist-induced food intake in rats in vivo
This represents a major simplification from the native relaxin-3 molecule (two chains, three disulfide bonds) to a drug-like single-chain peptide.
Key Numbers
How They Did This
Researchers used peptide stapling (incorporating non-natural amino acids to lock the peptide into a helical shape) to design simplified B-chain-only analogues of relaxin-3. The lead compound was tested for RXFP3 binding affinity, selectivity, antagonist potency, and serum stability in vitro. In vivo efficacy was confirmed by measuring food intake in rats after central RXFP3 agonist administration.
Why This Research Matters
Obesity treatment needs new mechanisms beyond GLP-1 receptor agonists. The relaxin-3/RXFP3 system controls appetite and motivation at the brain level, making it a compelling target. This study overcomes a major structural hurdle in relaxin-3 drug development, producing the first drug-like RXFP3 antagonist with proven in vivo activity.
The Bigger Picture
While GLP-1 receptor agonists dominate the current obesity treatment landscape, the relaxin-3/RXFP3 system represents an entirely different approach targeting the brain's motivation and feeding circuits. If RXFP3 antagonists can be developed into drugs, they could complement or offer alternatives to existing anti-obesity peptide therapies.
What This Study Doesn't Tell Us
This is early-stage preclinical work. The peptide was tested only in rats for a single behavioral endpoint (food intake). Pharmacokinetics, toxicity, brain penetration with peripheral dosing, and long-term efficacy have not been assessed. The peptide still requires injection (central administration in this study), and oral bioavailability is unknown.
Questions This Raises
- ?Can this RXFP3 antagonist cross the blood-brain barrier when administered peripherally, or will it need central delivery?
- ?Would combining RXFP3 antagonism with GLP-1 receptor agonism produce additive weight loss through complementary mechanisms?
- ?Does chronic RXFP3 blockade affect other relaxin-3-regulated behaviors like arousal and reward-seeking?
Trust & Context
- Key Stat:
- 12× more stable Serum stability improvement of the new stapled RXFP3 antagonist compared to the previous best linear antagonist
- Evidence Grade:
- This is an early-stage medicinal chemistry and preclinical pharmacology study. The peptide design is rigorous and the in vivo proof-of-concept is promising, but this is far from clinical application.
- Study Age:
- Published in 2025 in ACS Medicinal Chemistry Letters, this is a very recent advance in relaxin-3 peptide drug development.
- Original Title:
- Design and Synthesis of a Structurally Stabilized B‑Chain Antagonist Targeting Relaxin Family Peptide Receptor 3 (RXFP3).
- Published In:
- ACS medicinal chemistry letters, 16(11), 2294-2300 (2025)
- Authors:
- Wu, Hongkang(3), Praveen, Praveen, Riches, Isabelle, Suresh, Devika P, Gil-Miravet, Isis, Navarro-Sánchez, Mónica, Olucha-Bordonau, Francisco E, Rosengren, K Johan, Bathgate, Ross A D, Hossain, Mohammed Akhter
- Database ID:
- RPEP-14191
Evidence Hierarchy
Frequently Asked Questions
What is relaxin-3 and why does it matter for obesity?
Relaxin-3 is a brain peptide that increases appetite and drives reward-seeking behavior by activating the RXFP3 receptor. Blocking this receptor could reduce overeating at the neurological level, representing a fundamentally different approach to obesity treatment than drugs like semaglutide.
What is peptide stapling?
Stapling is a chemical technique that locks a peptide into a specific 3D shape (usually a helix) using non-natural amino acid bridges. This makes the peptide more potent, more stable in the body, and potentially better as a drug candidate than its floppy, unstructured counterpart.
Read More on RethinkPeptides
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Cite This Study
https://rethinkpeptides.com/research/RPEP-14191APA
Wu, Hongkang; Praveen, Praveen; Riches, Isabelle; Suresh, Devika P; Gil-Miravet, Isis; Navarro-Sánchez, Mónica; Olucha-Bordonau, Francisco E; Rosengren, K Johan; Bathgate, Ross A D; Hossain, Mohammed Akhter. (2025). Design and Synthesis of a Structurally Stabilized B‑Chain Antagonist Targeting Relaxin Family Peptide Receptor 3 (RXFP3).. ACS medicinal chemistry letters, 16(11), 2294-2300. https://doi.org/10.1021/acsmedchemlett.5c00489
MLA
Wu, Hongkang, et al. "Design and Synthesis of a Structurally Stabilized B‑Chain Antagonist Targeting Relaxin Family Peptide Receptor 3 (RXFP3).." ACS medicinal chemistry letters, 2025. https://doi.org/10.1021/acsmedchemlett.5c00489
RethinkPeptides
RethinkPeptides Research Database. "Design and Synthesis of a Structurally Stabilized B‑Chain An..." RPEP-14191. Retrieved from https://rethinkpeptides.com/research/wu-2025-design-and-synthesis-of
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkPeptides research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.