Scientists at the University of Utah have found an enzyme that can reshape diabetes and obesity drugs by converting them into tight ring structures, potentially making them more durable and effective in the body.
The enzyme, called PapB, works by linking the ends of therapeutic peptides into compact rings through a process called macrocyclization. This discovery could enhance GLP-1 medications like semaglutide, the active ingredient in Ozempic and Wegovy, by making them work harder and last longer before the body breaks them down.
Karsten Eastman, a research associate in the university's chemistry department and co-founder of Sethera Therapeutics, explained the challenge peptides pose. "Peptides are extremely difficult to work with because they have a lot of reactive chemical handles," he said. "What we show in the study is an enzymatic method using a tiny molecular machine to modify peptides in extremely controlled ways, enabling what we believe will be next generation peptide therapeutics."
Ring-shaped peptides offer significant advantages over their linear counterparts. They are more stable, remain active longer in the body, and interact better with their biological targets. The traditional method of closing peptide chains into rings has required complex chemical techniques, especially late in drug development.
PapB provides a cleaner alternative. The enzyme forms a precise bond linking the ends of a peptide without needing extra sequences that other enzymes typically require to recognize their targets. In laboratory experiments published in ACS Bio and Med Chem Au, the team successfully used PapB to connect the ends of GLP-1-like peptides, creating a sulfur-carbon bond called a thioether.
Jake Pedigo, lead author of the paper and a graduate student in the lab, noted the enzyme's unexpected flexibility. "It didn't need the usual leader sequence, and it still worked even when we swapped in unusual amino acids," he said. "That combination of precision and adaptability makes PapB a practical tool for peptide engineering."
One major problem with peptide-based drugs is that the body rapidly breaks them down. Proteases, enzymes that recycle proteins, cut peptides into individual amino acids, shortening their effectiveness. By converting peptides into ring shapes, the modified molecules essentially hide from these common proteases, potentially extending how long the drug works.
Eastman and chemistry professor Vahe Bandarian co-founded Sethera last year to bring their research into real-world applications, with support from the National Institutes of Health. The university recognized their work by naming them 2025 Founders of the Year for developing the PolyMacrocyclic Peptide Discovery Platform.
The potential impact extends beyond Ozempic itself. "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."
The team tested PapB on three different GLP-1-like peptides, and in each case the enzyme successfully converted linear molecules into ring-shaped versions. These results suggest PapB could function as a flexible, plug-and-play tool for modifying peptides even at late stages of drug development, potentially opening the door to more stable, more targeted therapies that are easier to manufacture.
Author Jessica Williams: "This is exactly the kind of unglamorous enzyme work that could quietly transform how we make better versions of billion-dollar drugs without starting from scratch."
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