From the Bandarian Lab to a Utah Spinout: University of Utah Science Powers Enzymatic Makeovers for GLP-1-Like Peptides

SALT LAKE CITY, October 14, 2025 — A University of Utah team has shown that a radical enzyme can "tie off" therapeutic peptides into compact rings without the usual leader-sequence requirements, an advance now moving from campus to clinic-facing development through Utah spinout Sethera Therapeutics. The findings have been published in a paper in the prestigious ACS Bio & Med Chem Au Journal.

GLP-1 receptor agonists have transformed the treatment of diabetes and obesity, but peptide stability and tissue-targeting remain key challenges for next-generation incretin therapies. This enzymatic innovation addresses those limitations directly by offering a programmable modification strategy that can be applied late in drug development without extensive re-engineering.

The study's first author, Jacob Pedigo of the Vahe Bandarian Lab in the Department of Chemistry, used a variety of analytic methods to confirm clean C-terminal thioether macrocyclization on GLP-1-pathway analogs. In classical ribosomally synthesized and post-translationally modified peptide (RiPP) biosynthesis, enzymes depend on an N-terminal leader sequence in the peptide to dock to a cognate recognition element (RRE). The Utah team found that the rSAM maturase PapB can operate leader-independently, still forging the intended thioether ring even when the RRE domain is deleted or when the leader sequence is swapped for an unrelated one. That unusual combination—mechanistic specificity with striking substrate promiscuity—eases translation because researchers can retrofit the same biocatalyst across many sequences with minimal re-engineering.

"From a bench perspective, the surprise was how far we could push the enzyme—no native leader, swapped leaders, non-canonical residues—and still see clean, single-ring products. That combination of tolerance and control makes PapB feel like a practical tool, not just a cool mechanism." – Jake Pedigo, First Author

The implications for patient-facing outcomes are direct. A compact C-terminal ring can block proteases, stabilize a preferred receptor-binding pose, and serve as a programmable "handle" for half-life extension or tissue targeting—features that are central to future incretin medicines. With Utah-born expertise in enzymology and peptide chemistry, the pathway from bench to bedside becomes shorter and more capital-efficient.

"Utah has a deep bench in enzymology. What's exciting here is that PapB delivers specific chemistry while relaxing sequence rules that usually slow translation. That opens a practical path to fine-tune approved peptide scaffolds late in development—stability, signaling bias, even tissue targeting—using a single, well-behaved enzyme." – Vahe Bandarian, Professor of Chemistry; CSO, Sethera Therapeutics

Reflecting the U's commitment to research commercialization, the University of Utah holds patent interests in the findings, and Utah-based Sethera Therapeutics has been co-founded by Vahe Bandarian, PhD (CSO) and Karsten A. S. Eastman, PhD (CEO) to advance the technology. The work was supported by the NIH (R35 GM126956; T32 GM122740), highlighting how federal investment in Utah science fuels local companies and, ultimately, drives clinical innovation.