Researchers at the University of Utah have demonstrated that a radical enzyme can cyclize therapeutic peptides into compact rings without the usual leader-sequence requirements, a finding that could streamline the development of next-generation GLP-1 receptor agonists for diabetes and obesity. The work, published in ACS Bio & Med Chem Au, is now being advanced by Utah spinout Sethera Therapeutics.
GLP-1 receptor agonists have transformed the treatment of diabetes and obesity, but peptide stability and tissue-targeting remain key challenges. 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 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.
“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,” said Pedigo. “That combination of tolerance and control makes PapB feel like a practical tool, not just a cool mechanism.”
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 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,” said Vahe Bandarian, Professor of Chemistry and CSO of Sethera Therapeutics. “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.”
Reflecting the University of Utah's commitment to research commercialization, the university holds patent interests in the findings, and Utah-based Sethera Therapeutics has been co-founded by Bandarian and Karsten A. S. Eastman (CEO) to advance the technology. The work was supported by the NIH (R35 GM126956; T32 GM122740). More information about partnering with Sethera is available at https://setheratx.com/.
