New Long-Acting Peptide Combined With GLP-1 Drugs Achieves 41% Weight Loss in Obese Rats | Research

The takeaway

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.

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

What the researchers 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.

Why it 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 numbers in context

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 the study worked

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.

Who was studied

Diet-induced obese (DIO) rats; in vitro receptor activation assays

What this study cannot 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.

How to read the evidence

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.

When this study was published

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.

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.

Questions still open

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?

Common 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 the original research

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

View on PubMed ↗Publisher’s paper ↗

Citation

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