New Long-Acting Peptide Combined With GLP-1 Drugs Achieves 41% Weight Loss in Obese Rats
A novel stapled peptide targeting amylin and calcitonin receptors achieved up to 41% weight loss in obese rats when combined with semaglutide or tirzepatide — far exceeding either drug alone.
Quick Facts
What This Study Found
Researchers designed UDA-6, a long-acting stapled peptide that potently activates both amylin (AMY3R) and calcitonin (CTR) receptors, using a novel on-resin Ugi macrocyclization chemistry based on salmon calcitonin. The stapled design enhanced helical stability and extended the half-life to support once-weekly dosing. In diet-induced obese rats, UDA-6 alone produced substantial weight loss and improved metabolic and liver parameters.
When combined with semaglutide or tirzepatide, UDA-6 achieved synergistic effects — up to 41% vehicle-adjusted body weight reduction and near-normalized liver fat profiles. This combination performance significantly exceeded what either drug class achieved alone.
Key Numbers
41% vehicle-adjusted body weight reduction (combination) · Balanced AMY3R + CTR activation · Once-weekly dosing pharmacokinetics · Near-normalized liver lipids · Synergistic with both semaglutide and tirzepatide
How They Did This
UDA-6 was designed using Ugi macrocyclization on a salmon calcitonin template to create a stapled (conformationally constrained) peptide. Receptor activation was measured at AMY3R and CTR. Pharmacokinetics were characterized to determine dosing frequency. Efficacy was tested in diet-induced obese (DIO) rats as monotherapy and in combination with semaglutide or tirzepatide. Endpoints included body weight change, metabolic parameters, and liver lipid profiles.
Why This Research Matters
The 41% body weight reduction in obese rats represents an extraordinary level of efficacy that, if translatable to humans, would far exceed current obesity treatments. This study demonstrates that combining amylin/calcitonin receptor signaling with GLP-1 pathway activation creates synergistic weight loss — opening a new frontier in multi-peptide obesity therapy. The Ugi macrocyclization platform also solves a major problem with amylin-based peptides: their tendency to aggregate and their short half-lives.
The Bigger Picture
The obesity drug pipeline is rapidly evolving from single-target GLP-1 drugs to multi-target combinations. While tirzepatide (dual GIP/GLP-1) and triple agonists (GLP-1/GIP/glucagon) are already in development, adding amylin/calcitonin signaling represents yet another complementary pathway. The 41% weight loss in rats — if even partially translatable — could approach the efficacy of bariatric surgery in pharmaceutical form. This study also showcases Ugi macrocyclization as a powerful new tool for designing long-acting peptide drugs.
What This Study Doesn't Tell Us
All efficacy data is from rats — weight loss percentages in rodents typically don't directly translate to humans. The combination therapy data, while impressive, needs safety assessment (GI tolerability of triple-pathway stimulation is a major concern). The Ugi macrocyclization is a novel chemistry that requires further manufacturing scale-up validation. No human pharmacokinetic or safety data exists. The 41% weight loss was in combination, not monotherapy.
Questions This Raises
- ?Will the 41% weight loss in rats translate to meaningful additional weight loss in humans already on GLP-1 drugs?
- ?Can patients tolerate the gastrointestinal effects of simultaneously stimulating amylin, calcitonin, and GLP-1 pathways?
- ?Could the Ugi macrocyclization platform be applied to stabilize other therapeutically important but unstable peptides?
Trust & Context
- Key Stat:
- 41% weight reduction Combining the new DACRA peptide UDA-6 with semaglutide or tirzepatide achieved 41% body weight reduction in obese rats — approaching bariatric surgery-level efficacy
- Evidence Grade:
- This is a preclinical study in diet-induced obese rats with in vitro pharmacology. The results are impressive but represent early-stage drug discovery. Translation from rodent weight loss to human efficacy requires extensive further development.
- Study Age:
- Published in 2026, this represents the cutting edge of multi-peptide obesity drug design, building on the success of GLP-1 and dual agonist drugs now in clinical use.
- Original Title:
- Development of a Long-Acting and Stapled Dual Amylin and Calcitonin Receptor Agonist as Monotherapy and Combination with GLP-1R Agonists for the Treatment of Obesity.
- Published In:
- Bioconjugate chemistry, 37(1), 169-179 (2026)
- Authors:
- Zhou, Yaqi(2), Xu, Pu, Lu, Jiang, Xu, Shujing, Qiu, Wenting, Ning, Xiao, Xu, Jiean, Zheng, Nan
- Database ID:
- RPEP-16611
Evidence Hierarchy
Frequently Asked Questions
What is a DACRA and how is it different from GLP-1 drugs?
A DACRA (dual amylin and calcitonin receptor agonist) activates two receptors related to the appetite-suppressing hormone amylin. GLP-1 drugs like semaglutide work through a completely different receptor. Combining a DACRA with GLP-1 drugs targets multiple hunger and metabolism pathways simultaneously — like attacking obesity from multiple angles at once — which explains the dramatic 41% weight loss seen in this study.
What does 'stapled' mean for a peptide drug?
Peptide drugs are chains of amino acids that normally flop around in solution, making them unstable and quickly destroyed by enzymes. 'Stapling' adds a chemical crosslink that locks the peptide into its active shape (a helix), making it more resistant to degradation and more potent. The Ugi macrocyclization technique used here is a new and efficient way to create these stapled peptides, potentially making it easier to develop long-acting peptide drugs.
Read More on RethinkPeptides
Related articles coming soon.
Cite This Study
https://rethinkpeptides.com/research/RPEP-16611APA
Zhou, Yaqi; Xu, Pu; Lu, Jiang; Xu, Shujing; Qiu, Wenting; Ning, Xiao; Xu, Jiean; Zheng, Nan. (2026). Development of a Long-Acting and Stapled Dual Amylin and Calcitonin Receptor Agonist as Monotherapy and Combination with GLP-1R Agonists for the Treatment of Obesity.. Bioconjugate chemistry, 37(1), 169-179. https://doi.org/10.1021/acs.bioconjchem.5c00558
MLA
Zhou, Yaqi, et al. "Development of a Long-Acting and Stapled Dual Amylin and Calcitonin Receptor Agonist as Monotherapy and Combination with GLP-1R Agonists for the Treatment of Obesity.." Bioconjugate chemistry, 2026. https://doi.org/10.1021/acs.bioconjchem.5c00558
RethinkPeptides
RethinkPeptides Research Database. "Development of a Long-Acting and Stapled Dual Amylin and Cal..." RPEP-16611. Retrieved from https://rethinkpeptides.com/research/zhou-2026-development-of-a-longacting
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.