Scientists engineered long-acting PYY analogs with superior Y2 receptor selectivity that, when combined with a GLP-1 agonist, achieved greater blood sugar and weight loss than GLP-1 treatment alone — with one candidate now in clinical trials.
PYY1875 entered clinical trialsA long-acting PYY analog engineered through variant screening and fatty acid modification has progressed to human testing for obesity
What the researchers found
Systematic variant screening of PYY3-36 identified key amino acids responsible for Y2 receptor selectivity, potency, and stability. Combined with fatty diacid derivatization (attaching a fatty acid chain for albumin binding and extended half-life), this produced highly selective, long-acting Y2 receptor agonists.
In preclinical models:
- The analogs improved glucose metabolism in diabetic db/db mice
- Combined with a long-acting GLP-1 receptor agonist, they showed superior blood glucose lowering in diabetic ZSF1 rats compared to GLP-1 alone
- The combination also produced greater body weight loss than GLP-1 alone in a high-fat diet-induced mouse obesity model
One analog, PYY1875, has progressed into clinical trials for obesity, validating the drug development approach.
Why it matters
GLP-1 drugs like semaglutide have transformed obesity treatment, but there is strong interest in combining them with other gut hormones for even greater efficacy. PYY acts through different brain circuits than GLP-1, suppressing appetite through complementary mechanisms. A long-acting PYY analog that can be combined with existing GLP-1 drugs could represent the next generation of obesity treatments — and one candidate is already in human trials. This is the same multi-hormone approach that led to tirzepatide (GLP-1/GIP dual agonist).
How the study worked
The researchers performed systematic variant screening of PYY3-36, substituting amino acids at each position to identify residues critical for Y2 receptor selectivity, potency, and peptide stability. Lead candidates were modified with fatty diacid derivatization to extend half-life through albumin binding. Analogs were tested in vitro for Y1, Y2, Y4, and Y5 receptor activity. In vivo efficacy was assessed in diabetic db/db mice (glucose metabolism), diabetic ZSF1 rats (blood glucose lowering in combination with GLP-1 agonist), and high-fat diet-induced obese mice (body weight loss, alone and combined with GLP-1 agonist).
What this study cannot tell us
All efficacy data is from animal models (db/db mice, ZSF1 rats, diet-induced obese mice), which may not fully predict human responses. The specific degree of improvement over GLP-1 alone is not quantified in the abstract. Clinical trial results for PYY1875 in humans are not yet available. The long-term safety profile of chronic Y2 receptor activation is unknown. Whether PYY analogs can match the dramatic weight loss seen with newer GLP-1 drugs in humans remains to be determined.
How to read the evidence
This is a preclinical drug development study published in Science Translational Medicine, with strong in vitro characterization and in vivo proof of concept across multiple animal models. The progression of PYY1875 to clinical trials validates the approach, but human efficacy and safety data are pending.
When this study was published
Published in 2025, this is cutting-edge research at the forefront of next-generation obesity drug development. Clinical trial results for PYY1875 are expected in the coming years.
The bigger picture
The obesity drug field is rapidly moving from single-hormone drugs (semaglutide targets GLP-1) to multi-hormone combinations (tirzepatide targets GLP-1+GIP, retatrutide targets GLP-1+GIP+glucagon). PYY represents yet another complementary hormone that could be added to this arsenal. This study published in Science Translational Medicine demonstrates a rigorous peptide engineering approach that could be applied to other gut hormones, accelerating the development of the next wave of metabolic drugs.
Questions still open
- Will PYY1875 demonstrate meaningful additional weight loss when combined with GLP-1 agonists in human clinical trials?
- Does long-term Y2 receptor activation have any adverse effects on mood, anxiety, or gut motility that could limit clinical use?
- Could a triple combination of GLP-1 + GIP + PYY agonists produce even greater metabolic benefits than any dual combination?
Common questions
What is PYY and how is it different from GLP-1?
Why can't natural PYY be used as a drug?
Read the original research
Variant screening of PYY3-36 leads to potent long-acting PYY analogs with superior Y2 receptor selectivity.
Science translational medicine, 17(791), eadq6392
Citation
Østergaard, Søren; Jessen, Carsten; Paulsson, Johan F; Kasimova, Marina A; Conde-Frieboes, Kilian W; Straarup, Ellen Marie; Skyggebjerg, Rikke Bjerring; Ynddal, Lars; Sanfridson, Annika; Wulff, Birgitte S; Chambers, Adam P. (2025). Variant screening of PYY3-36 leads to potent long-acting PYY analogs with superior Y2 receptor selectivity.. Science translational medicine, 17(791), eadq6392. https://doi.org/10.1126/scitranslmed.adq6392