Scientists discover new enzyme that could supercharge weight-loss drugs – Image for illustrative purposes only (Image credits: Unsplash)
Researchers at the University of Utah identified a novel enzyme called PapB that transforms linear peptide drugs into compact ring shapes. This process, known as macrocyclization, links the ends of peptides through a precise sulfur-carbon bond called a thioether. The discovery offers a pathway to create more durable versions of GLP-1 medications such as semaglutide, the active ingredient in Ozempic and Wegovy, which millions use for diabetes and obesity treatment.[1][2]
PapB Emerges as a Versatile Peptide Modifier
A team from the University of Utah’s Department of Chemistry uncovered PapB during studies of ribosomally synthesized and post-translationally modified peptides, or RiPPs. The enzyme, a radical S-adenosyl-L-methionine maturase, operates without the need for traditional leader sequences that guide most enzymes to their targets. Lead author Jake Pedigo, a graduate student in Vahe Bandarian’s lab, noted the unexpected flexibility of PapB. It handled peptides with nonstandard amino acids and varying motifs, forming cross-links between cysteine and aspartate or glutamate residues.[1][3]
Karsten Eastman, a research associate in the department and co-founder of Sethera Therapeutics, highlighted the challenge of working with peptides. “Peptides themselves can be extremely difficult to work with because they have a lot of reactive chemical handles,” Eastman said. Yet this reactivity allows precise biological functions. PapB provides an enzymatic solution superior to chemical methods, which often prove costly and imprecise during late-stage drug development.[4]
From Lab Tests to Therapeutic Analogues
The researchers tested PapB on native substrates like PapA before advancing to GLP-1 mimics. They engineered analogues of semaglutide, tirzepatide, and retatrutide by adding a C-terminal CSANDA motif to enable cyclization. In anaerobic conditions, PapB achieved complete conversion, shifting the peptides’ mass by two daltons to confirm thioether formation. Mass spectrometry verified the links, even with modifications like homocysteine substitutions.[3]…