University of Utah Enzyme Discovery Enables Programmable Peptide Modification for Next-Generation Diabetes and Obesity Treatments

University of Utah scientists have demonstrated that a radical enzyme can modify therapeutic peptides into compact rings without the usual leader-sequence requirements, an advancement now transitioning from academic research to clinical development through Utah-based Sethera Therapeutics. The findings, published in ACS Bio & Med Chem Au Journal, represent a significant step forward for next-generation incretin therapies used in diabetes and obesity treatment.

GLP-1 receptor agonists have revolutionized diabetes and obesity care, but peptide stability and tissue-targeting remain persistent challenges for improved incretin therapies. This enzymatic innovation directly addresses these limitations by providing a programmable modification strategy that can be implemented late in drug development without extensive re-engineering of existing peptide scaffolds.

Jacob Pedigo of the Vahe Bandarian Lab in the Department of Chemistry used multiple analytical methods to confirm clean C-terminal thioether macrocyclization on GLP-1-pathway analogs. In traditional ribosomally synthesized and post-translationally modified peptide biosynthesis, enzymes require an N-terminal leader sequence in the peptide to dock to a cognate recognition element. The Utah team discovered that the rSAM maturase PapB can function leader-independently, still forming the intended thioether ring even when the RRE domain is deleted or when the leader sequence is replaced with an unrelated one.

This unusual combination of mechanistic specificity with substantial substrate promiscuity facilitates translation because researchers can apply the same biocatalyst across multiple sequences with minimal re-engineering. From a practical perspective, the enzyme demonstrated remarkable tolerance to various modifications while maintaining precise control over the final product formation.

The clinical implications are substantial. A compact C-terminal ring can block protease degradation, stabilize preferred receptor-binding conformations, and serve as a programmable attachment point for half-life extension or tissue targeting capabilities. These features are central to developing more effective incretin medicines with improved stability and targeted delivery.

Reflecting the University of Utah's commitment to research commercialization, the institution holds patent interests in the findings, and Sethera Therapeutics has been co-founded by Vahe Bandarian and Karsten A. S. Eastman to advance the technology. The work received support from the National Institutes of Health through grants R35 GM126956 and T32 GM122740, demonstrating how federal research investment fuels local company development and ultimately drives clinical innovation. For additional information about the technology and its applications, visit https://setheratx.com/.