University of Utah Enzyme Discovery Enables Programmable Peptide Modifications for Next-Generation Diabetes and Obesity Treatments
University of Utah researchers have developed an enzyme technology that can stabilize and enhance therapeutic peptides for diabetes and obesity treatments, with the innovation now advancing toward clinical development through spinout company Sethera Therapeutics.
University of Utah scientists have demonstrated that a radical enzyme can modify therapeutic peptides into compact rings without traditional sequence requirements, representing a significant advancement for next-generation diabetes and obesity treatments. The research, published in ACS Bio & Med Chem Au Journal, shows how the enzyme PapB can create C-terminal thioether macrocyclization on GLP-1 pathway analogs, addressing key stability and targeting challenges that have limited current incretin therapies.
GLP-1 receptor agonists have revolutionized diabetes and obesity treatment, but peptide stability and tissue-targeting remain persistent obstacles for improved therapies. The Utah team's enzymatic innovation directly confronts these limitations by providing a programmable modification strategy that can be implemented late in drug development without extensive re-engineering. First author Jacob Pedigo of the Vahe Bandarian Lab used multiple analytical methods to confirm clean macrocyclization on GLP-1 analogs, revealing that the rSAM maturase PapB operates independently of traditional leader sequences.
In conventional ribosomally synthesized and post-translationally modified peptide biosynthesis, enzymes typically require an N-terminal leader sequence to dock to a recognition element. The Utah researchers discovered that PapB maintains its function even when the recognition domain is deleted or when the leader sequence is replaced with unrelated sequences. This combination of mechanistic specificity with substrate flexibility simplifies translation, allowing researchers to apply the same biocatalyst across multiple sequences with minimal adjustments.
The practical implications for patient outcomes are substantial. A compact C-terminal ring can inhibit protease degradation, stabilize preferred receptor-binding configurations, and serve as a programmable attachment point for half-life extension or tissue targeting—all critical features for future incretin medications. The technology's ability to fine-tune approved peptide scaffolds late in development using a single, well-characterized enzyme represents a more capital-efficient pathway from laboratory research to clinical application.
Reflecting the University of Utah's commitment to research commercialization, the institution holds patent interests in the findings, and Utah-based Sethera Therapeutics has been co-founded to advance the technology toward clinical development. The work received support from the National Institutes of Health, demonstrating how federal research investment fuels local company formation and drives clinical innovation. For additional information about the technology platform, visit https://setheratx.com/.