University of Utah Enzyme Discovery Enables Programmable Modification of GLP-1 Peptides

A University of Utah research team has demonstrated that a radical enzyme can modify therapeutic peptides into compact rings without the typical leader-sequence requirements, an advancement now progressing toward clinical development through Utah spinout Sethera Therapeutics. The findings, published in ACS Bio & Med Chem Au Journal, address key challenges in peptide stability and tissue-targeting for next-generation incretin therapies like GLP-1 receptor agonists, which have revolutionized diabetes and obesity treatment but face limitations in drug development.

The enzymatic innovation offers a programmable modification strategy that can be applied late in drug development without extensive re-engineering, potentially accelerating the pathway from bench to bedside. First author Jacob Pedigo of the Vahe Bandarian Lab in the Department of Chemistry used various analytical methods to confirm clean C-terminal thioether macrocyclization on GLP-1-pathway analogs, revealing that the rSAM maturase PapB can operate leader-independently while still forming the intended thioether ring.

This unusual combination of mechanistic specificity with substrate promiscuity eases translation because researchers can apply the same biocatalyst across many sequences with minimal re-engineering. The enzyme maintained functionality even when the recognition element domain was deleted or when the leader sequence was swapped for an unrelated one, demonstrating remarkable tolerance while producing clean, single-ring products.

The implications for patient outcomes are significant, as a compact C-terminal ring can block proteases, stabilize preferred receptor-binding poses, and serve as a programmable handle for half-life extension or tissue targeting. These features are central to future incretin medicines and could enhance therapeutic efficacy while reducing development timelines. The University of Utah holds patent interests in the findings, and the technology has been licensed exclusively to Sethera Therapeutics, which aims to advance the platform toward clinical applications.

The work was supported by National Institutes of Health grants R35 GM126956 and T32 GM122740, highlighting how federal investment in Utah science fuels local companies and drives clinical innovation. For more information about the technology and its applications, visit https://setheratx.com/.