Peptide engineering created a PYY analog with 14+ hour half-life that, combined with a GLP-1 agonist, produced excellent weight loss and glucose control in obese mice.
>14h half-lifeengineered PYY analog predicting once-weekly human dosing, combined with GLP-1 for surgery-mimicking multi-hormone obesity treatment
What the researchers found
The native PYY peptide has a very short half-life, making it impractical as a medication. Using combined peptide stapling and PEG-fatty acid conjugation, the researchers created potent PYY analogs that activate the NPY2 receptor and have rat half-lives exceeding 14 hours.
The 14-hour rat half-life is expected to translate to a human half-life suitable for once-weekly dosing, which would be practical for patients.
The lead candidate (compound 22) combined with a long-acting GLP-1 analog showed excellent efficacy in a diet-induced obesity mouse model for three key outcomes: glucose control, food intake reduction, and body weight loss. This combination approach mimics the hormonal changes seen after bariatric surgery.
Why it matters
Bariatric surgery increases both GLP-1 and PYY, which likely contributes to its exceptional weight loss results. Recreating this hormonal combination pharmacologically could give patients surgery-level benefits without the risks of an operation.
The engineering approach (stapling + PEG-fatty acid) is a significant technical achievement that solved PYY's short half-life problem.
The numbers in context
>14h rat half-life; compound 22 + GLP-1 analog; excellent glucose/food intake/weight loss outcomes in DIO mice
How the study worked
Researchers used peptide stapling and PEG-fatty acid conjugation to engineer PYY analogs. They measured NPY2R potency, pharmacokinetics in rats, and in vivo efficacy in diet-induced obesity mice. The lead compound was tested alone and in combination with a long-acting GLP-1 analog.
Who was studied
Diet-induced obesity mice; rat pharmacokinetics
What this study cannot tell us
This was a mouse study. The predicted human half-life for once-weekly dosing needs to be confirmed in human pharmacokinetic studies.
Long-term efficacy and safety of PYY/GLP-1 combination therapy have not been assessed. The nausea and GI side effects common with gut hormone drugs were not specifically evaluated.
How to read the evidence
Moderate evidence from pharmacokinetic and mouse efficacy studies. Strong peptide engineering but human data needed.
When this study was published
Published in 2020. Multi-hormone obesity drug development has accelerated, with tirzepatide (dual GIP/GLP-1) approved since.
The bigger picture
Bariatric surgery increases both GLP-1 and PYY, which likely drives its exceptional results. This engineered PYY analog could recreate the PYY component pharmacologically. Combined with existing GLP-1 drugs, it could provide surgery-level weight loss without the operating room.
Questions still open
- Will the predicted once-weekly human dosing be confirmed in clinical pharmacokinetic studies?
- Does the PYY/GLP-1 combination produce more nausea than GLP-1 alone?
- Could triple combinations (PYY + GLP-1 + glucagon agonist) further improve outcomes?
Common questions
Why combine PYY with GLP-1 drugs?
How was the short half-life problem solved?
Read the original research
Engineering of a Potent, Long-Acting NPY2R Agonist for Combination with a GLP-1R Agonist as a Multi-Hormonal Treatment for Obesity.
Journal of medicinal chemistry, 63(17), 9660-9671
Citation
Lear, Sam; Pflimlin, Elsa; Zhou, Zhihong; Huang, David; Weng, Sharon; Nguyen-Tran, Van; Joseph, Sean B; Roller, Shane; Peterson, Scott; Li, Jing; Tremblay, Matthew; Schultz, Peter G; Shen, Weijun. (2020). Engineering of a Potent, Long-Acting NPY2R Agonist for Combination with a GLP-1R Agonist as a Multi-Hormonal Treatment for Obesity.. Journal of medicinal chemistry, 63(17), 9660-9671. https://doi.org/10.1021/acs.jmedchem.0c00740