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]
These experiments demonstrated leader-independent activity. A truncated version of PapB lacking its recognition element still processed substrates efficiently at low concentrations. Pedigo expressed surprise at the enzyme’s adaptability: “We were surprised by how flexible the enzyme turned out to be. It didn’t need the usual leader sequence, and it still worked even when we swapped in unusual amino acids.”[5]
Linear vs. Cyclic: A Stability Edge
Ring formation rigidifies peptides, blocking exoproteases that degrade linear chains from the ends. This concealment extends half-life from minutes to hours or longer, amplifying therapeutic impact. Cyclic structures also reduce conformational flexibility, potentially improving receptor binding for GLP-1 drugs that mimic gut hormones to curb appetite and regulate blood sugar.[2]
| Feature | Linear Peptides (e.g., Standard Semaglutide) | Cyclic Peptides via PapB |
|---|---|---|
| Protease Resistance | Vulnerable to breakdown | Protected by ring structure |
| Half-Life | Short duration | Extended activity |
| Modification Needs | Leader sequences required | Leader-independent |
| Drug Compatibility | Complex synthesis | Late-stage enzymatic tweak |
Eastman emphasized this advantage: “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 break down peptides. This would enable the longer half-life.”[1]
Implications for Diabetes and Obesity Care
GLP-1 drugs like Ozempic transformed treatment by promoting sustained weight loss and glycemic control. PapB could refine these backbones further. Eastman described it as “a clean, late-stage enzymatic step that can make those molecules work even harder,” tuning stability and signaling without disrupting established structures.[4]
The study appeared in ACS Bio & Med Chem Au on October 14, 2025, supported by National Institute of General Medical Sciences grants. While lab results show promise, clinical translation remains ahead. Enhanced durability might reduce dosing frequency, improving patient adherence for chronic conditions.
Toward Commercial Realization
Sethera Therapeutics, co-founded by Bandarian and Eastman, licensed the technology from the university. Named 2025 Founders of the Year by Utah’s Technology Licensing Office, the company advances the PolyMacrocyclic Peptide platform. This positions PapB for broader peptide engineering beyond GLP-1s.[1]
The work underscores enzymes’ role in precision medicine. As obesity rates climb, tools like PapB could deliver more effective, resilient therapies. Researchers continue optimizing its applications, potentially reshaping how peptide drugs combat metabolic diseases.
