Researchers at the University of Utah have identified an enzyme called PapB that can reshape therapeutic peptides, a type of protein-like drug, by joining their ends into a tight ring. This process, known as macrocyclization, creates compact structures that can improve how these drugs work in the body.
The discovery could be particularly useful in boosting GLP-1 drugs such as Ozempic and semaglutide, the active ingredient in Wigovy, which are widely used to treat diabetes and obesity. By converting these drugs into a ring-like form, scientists may be able to make them more durable and effective.
Why cyclic peptides are important for drug performance
Cyclic peptides have several advantages over open chain peptides. These structures are more stable, remain active longer, and are able to interact better with biological targets, said co-author Karsten Eastman, a researcher in the university’s Department of Chemistry and CEO and co-founder of Sethera Therapeutics.
“Peptides themselves can be very difficult to work with because they have a lot of highly reactive chemical handles. But this is what makes peptides so great in biology. You can get the type of reaction you want in the body, but it’s difficult to modify them in very specific ways,” said Eastman, who holds a Ph.D. In 2023, in the lab of Utah chemistry professor Vahe Bandalian. “What we demonstrate in this study is an enzymatic method that uses small molecular machines to modify or supermodify peptides in a highly controlled manner, enabling what we believe will be the next generation of peptide therapeutics.”
Eastman and Vandalian co-founded Sethera last year with funding from the National Institutes of Health to translate their discoveries into real-world applications. Their work was recently recognized by the University’s Office of Technology Licensing, where they were named 2025 Founders of the Year for the development of the polycyclic peptide (pMCP) discovery platform.
An easier alternative to traditional chemical methods
Closing peptide chains into rings has traditionally required complex and expensive chemical techniques, especially when attempted late in drug development. PapB offers a cleaner and more efficient approach. The enzyme forms precise bonds connecting the ends of peptides without the need for additional “leader” sequences that are normally required for enzymes to recognize their targets.
In a study published in ACS Bio & Med Chem AuThe researchers used PapB, a “radical SAM” (S-adenosyl-L-methionine) enzyme, to connect the ends of the GLP-1-like peptide. This bond forms a sulfur-carbon bond called a thioether. Laboratory experiments confirmed that PapB can successfully create these ring structures even when the peptides contain non-standard building blocks commonly used in modern incretin drugs.
Flexible enzymes act on complex drug molecules
“We were surprised by how flexible the enzyme turned out to be,” said Jake Pedigo, first author of the paper and a graduate student in Vandalian’s lab. “No conventional leader sequence was required and it worked even when unusual amino acids were replaced. This combination of precision and adaptability makes PapB a practical tool for peptide engineering.”
Although previous work from the same laboratory had introduced this ring-forming strategy, the latest study clearly proves its practical potential. The researchers tested PapB with three different GLP-1-like peptides, and in each case the enzyme converted the linear molecule into a circular version. These results demonstrate that PapB can serve as a flexible plug-and-play tool to modify peptides even at late stages of drug development.
Extend drug life by avoiding degradation
“The new research brings together a large body of research in new ways, making it possible to use enzymatic methods in particular to make certain types of modifications to already commercially available therapeutics that no one else has been able to achieve,” Eastman said. The researchers also found that this approach could improve the stability of the peptides, increasing the efficacy of these drugs.
One of the big challenges with peptide-based drugs is that they break down quickly in the body. Proteases, enzymes that recycle proteins, can rapidly cleave peptides into individual amino acids, reducing their effectiveness.
“There are peptides that may have a good biological response, but if that biological response only lasts a few minutes, all of a sudden there’s no better therapy,” Eastman said. “By joining the ends together using this enzymatic method, you are essentially hiding the peptide from some of the most common proteases in the body that break down peptides. This allows for a longer half-life.”
Broad potential of next-generation GLP-1 drugs
Traditional chemical approaches are not always compatible with delicate peptide drugs, and many enzymes previously considered useful required additional sequences to function. By showing that PapB functions without these requirements, the researchers demonstrated the potential applicability of PapB to a variety of peptide drugs.
This flexibility could open the door to new treatments that are more stable, more targeted, and easier to manufacture.
“Big Pharma’s GLP-1 backbone is already good,” Eastman said. “What we’re adding is a clean, late-stage enzymatic step that allows these molecules to work even more powerfully. By attaching small, well-defined rings, we can tune the drug’s duration, stability, and even how the signal is delivered, while remaining compatible with the complex structures already in use.”
