Utah chemists discover enzyme that could help build next-generation GLP-1 drugs

Chemistry researchers at the University of Utah have uncovered an enzyme, dubbed PapB, that can “tie off” therapeutic peptides—protein-like drugs—into tight rings, a process known as macrocyclization.

This enzymatic trick could help drug developers make stronger, longer-lasting versions of GLP-1 medications, such as semaglutide—the active ingredient in Ozempic and Wegovy—used to treat diabetes and obesity, according to a study published this week.

Creating cyclic peptides is valuable because these ring structures make drugs more stable, last longer in the body, and even work better on their biological targets, according to co-author Karsten Eastman, a research associate in the univeristy's Department of Chemistry and CEO and co-founder of Sethera Therapeutics.

“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, a coauthor on the study, launched Sethera last year to commercialize their discoveries made at the university with funding from the National Institutes of Health. Their efforts were honored last week by the university’s Technology Licensing Office, naming them the 2025 Founders of the Year for developing their PolyMacrocyclic Peptide (pMCP) Discovery Platform.

Traditional chemical methods for closing peptide rings are expensive and tricky to complete late in drug development. The newly discovered enzyme offers a simpler, cleaner alternative that naturally forms a precise chemical bond that closes the peptide chain into a ring without the extra “leader” sequences that most enzymes require to recognize their targets.

The new study, published in ACS Bio & Med Chem Au, describes how the team used a “radical SAM” (S-adenosyl-L-methionine) enzyme called PapB to connect the ends of GLP-1–like peptides through a sulfur-carbon bond, known as thioether. Laboratory tests confirmed the formation of these rings, even when the peptides included nonstandard building blocks found in many modern incretin drugs used to treat diabetes.

“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.”

In previous published studies, the lab had already outlined this method of tying off peptides.  Their latest findings offer a proof of concept demonstrating how useful this method could be. The researchers applied PapB to three GLP-1-like peptides, and in each case, the enzyme converted the open peptide into a ringed version. These results suggest that PapB can serve as a plug-and-play biocatalyst for reshaping peptides late in drug development.

“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 team’s method could also improve the stability of the peptides, and thus enhance their therapeutic effectiveness.

The human body is extremely efficient at recycling proteins thanks to the presence of proteases, enzymes that digest peptides into individual amino acids.

“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.”

Traditional chemical methods for closing rings are not always compatible with delicate peptide drugs. Enzymes like PapB offer a more precise solution—but until now, most were thought to require the leader sequence to function.

By demonstrating that PapB doesn’t require the leader sequence to function, the researchers demonstrate that it can be used on a wide range of peptides, potentially enabling new therapeutic designs that are sturdier, more targeted and easier to make.

“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.”

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This study appeared Oct. 14 under the title, “Leader-Independent C‑Terminal Modification by a Radical S‑Adenosyl‑L‑methionine Maturase Enables Macrocyclic GLP-1-Like Peptides,” in the journal ACS Bio & Med Chem Au, published by the American Chemical Society. This research was supported by grants from the National Institute of General Medical Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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