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.
12× more stableSerum stability improvement of the new stapled RXFP3 antagonist compared to the previous best linear antagonist
What the researchers 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.
Why it 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.
How the study worked
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.
What this study cannot 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.
How to read the evidence
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.
When this study was published
Published in 2025 in ACS Medicinal Chemistry Letters, this is a very recent advance in relaxin-3 peptide drug development.
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.
Questions still open
- 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?
Common questions
What is relaxin-3 and why does it matter for obesity?
What is peptide stapling?
Read the original research
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
Citation
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