University of Utah scientists report that a radical SAM enzyme known as PapB can join the ends of certain therapeutic peptides to form stable, ring-shaped structures. In experiments described in ACS Bio & Med Chem Au, the enzyme macrocyclized GLP-1-like peptides—including versions containing nonstandard amino acids found in some modern incretin drugs—an approach the researchers say could help make GLP-1 medicines such as semaglutide (Ozempic and Wegovy) more resistant to breakdown.
A University of Utah research team led by chemistry professor Vahe Bandarian has identified an enzyme called PapB that can reshape peptide drugs by linking their ends into compact rings—a process known as macrocyclization.
In the study, the researchers describe PapB as a “radical SAM” (S-adenosyl-L-methionine) enzyme that forms a sulfur–carbon thioether bond to close a peptide chain into a ring. The team reports that this enzymatic approach can create the ring without requiring extra “leader” sequences that many peptide-modifying enzymes typically need for target recognition.
Laboratory experiments tested PapB on three different GLP-1-like peptides. The researchers say the enzyme converted each linear peptide into a ring-shaped form, and that the reaction still worked even when the peptides included nonstandard amino-acid building blocks used in some modern incretin drugs.
“We were surprised by how flexible the enzyme turned out to be,” lead author Jake Pedigo said. “It didn’t need the usual leader sequence, and it still worked even when we swapped in unusual amino acids.”
The University of Utah researchers argue that improving peptide stability matters because many peptide-based drugs can be broken down quickly in the body by proteases. They say the ring-forming modification could help shield peptides from this kind of degradation—an attribute they frame as potentially relevant for GLP-1 medicines such as semaglutide, the active ingredient in Ozempic and Wegovy, which are used to treat diabetes and obesity.
The work was published in the journal ACS Bio & Med Chem Au.
