The discovery could be especially useful for enhancing GLP-1 medications such as semaglutide, the active ingredient in Ozempic and Wegovy, which are widely used to treat diabetes and obesity. By converting these drugs into ring-shaped forms, scientists may be able to make them more durable and effective.

Why Cyclic Peptides Matter for Drug Performance

Ring-shaped peptides offer several advantages over their open-chain counterparts. According to co-author Karsten Eastman, a research associate in the university’s Department of Chemistry and CEO and co-founder of Sethera Therapeutics, these structures are more stable, remain active longer, and can better interact with their biological targets.

“Peptides themselves can be extremely difficult to work with because they have a lot of reactive chemical handles. But this is what makes them so great in biology. You can get the type of reaction that you want in the body, but it’s difficult to modify them in hyper-specific ways,” said Eastman, who completed his Ph.D. in 2023 in the lab of Utah chemistry professor Vahe Bandarian. “What we show in the study is an enzymatic method — using a tiny molecular machine to modify or hyper modify peptides in extremely controlled ways — enabling what we believe will be next generation peptide therapeutics.”

Eastman and Bandarian co-founded Sethera last year to bring their discoveries toward real-world applications, supported by funding from the National Institutes of Health. Their work was recently recognized by the university’s Technology Licensing Office, which named them 2025 Founders of the Year for developing the PolyMacrocyclic Peptide (pMCP) Discovery Platform.

A Simpler Alternative to Traditional Chemical Methods

Closing peptide chains into rings has traditionally required complex and costly chemical techniques, especially when attempted late in drug development. PapB provides a cleaner and more efficient approach. The enzyme forms a precise bond that links the ends of a peptide without needing extra “leader” sequences, which are typically required for enzymes to recognize their targets.

In the study, published in ACS Bio & Med Chem Au, the team used PapB, a “radical SAM” (S-adenosyl-L-methionine) enzyme, to connect the ends of GLP-1-like peptides. The linkage forms a sulfur-carbon bond called a thioether. Laboratory experiments confirmed that PapB successfully created these ring structures, even when the peptides included nonstandard building blocks commonly used in modern incretin drugs.

Flexible Enzyme Works With Complex Drug Molecules

“We were surprised by how flexible the enzyme turned out to be,” said Jake Pedigo, lead author of the paper and a graduate student in the Bandarian lab. “It didn’t need the usual leader sequence, and it still worked even when we swapped in unusual amino acids. That combination of precision and adaptability makes PapB a practical tool for peptide engineering.”

Earlier studies from the same lab had introduced this ring-forming strategy, but the latest research provides clear proof of its practical potential. The team tested PapB on three different GLP-1-like peptides, and in each case, the enzyme converted the linear molecules into ring-shaped versions. These results indicate that PapB could function as a flexible, plug-and-play tool for modifying peptides even at late stages of drug development.

Extending Drug Lifespan by Avoiding Breakdown

“The new study ties together a significant amount of research in a new way, enabling an already on-the-market therapeutic to have a specific type of modification that no one has been able to achieve, especially using an enzymatic method,” Eastman said. The researchers also found that this approach could improve peptide stability, potentially increasing how well these drugs work.

One major challenge for peptide-based drugs is that the body quickly breaks them down. Proteases, enzymes that recycle proteins, can rapidly cut peptides into individual amino acids, shortening their effectiveness.

“You have these peptides that could have a great biological response, but if that biological response only lasts minutes, then all of a sudden you don’t have a good therapeutic,” Eastman said. “By using this enzymatic method to tie off the ends, we are essentially hiding the peptide from some of the most common proteases in the body — which are what breaks down peptides. This would enable the longer half-life.”

Broad Potential for Next-Generation GLP-1 Drugs

Traditional chemical approaches are not always compatible with delicate peptide drugs, and many enzymes previously thought useful required additional sequences to function. By showing that PapB works without these requirements, the researchers demonstrated its potential to be applied across a wide variety of peptide drugs.

This flexibility could open the door to new therapies that are more stable, more targeted, and easier to manufacture.

“Big pharma’s GLP-1 backbones are already excellent,” Eastman said. “What we’re adding is a clean, late-stage enzymatic step that can make those molecules work even harder. By installing a small, well-defined ring, we can tune how long the drug lasts, how stable it is, and even how it signals — all while staying compatible with the complex structures already in use.”